|
|
|
|
e.g., |
|
|
e.g., tri-iodothyronine |
2 weeks |
|
|
2 weeks |
|
|
|
|
|
|
|
corticosteroids, sulfonamides tolbutamide, perchlorate phenylbutazone lithium |
1 week 1 week 1-2 weeks 4 weeks |
| Concomitant Drug Class: Drug Name | Effect on Concentration of Amprenavir or Concomitant Drug | Clinical Comment |
|
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||
|
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|
|
|
|
|
|
|
|
|
Appropriate doses of the combinations with respect to safety and efficacy have not been established. |
|
|
|
Appropriate doses of the combinations with respect to safety and efficacy have not been established. |
|
|
|
An increased rate of adverse events has been observed. Appropriate doses of the combinations with respect to safety and efficacy have not been established. |
|
|
|
Appropriate doses of the combination with respect to safety and efficacy have not been established. |
|
|
||
|
|
|
Use with caution. Increased exposure may be associated with life-threatening reactions such as cardiac arrhythmias. Therapeutic concentration monitoring, if available, is recommended for antiarrhythmics. |
|
|
Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored. | |
|
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|
|
|
|
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|
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|
↑Rifabutin and rifabutin metabolite |
|
|
|
↑Benzodiazepines | Clinical significance is unknown. A decrease in benzodiazepine dose may be needed. |
|
|
↑Calcium channel blockers | Use with caution. Clinical monitoring of patients is recommended. |
|
|
↓Amprenavir | Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations. |
|
|
|
Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations. |
|
|
|
Use the lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as fluvastatin or pravastatin. |
|
|
↑Immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents. |
|
|
|
|
|
|
↓Methadone | Data suggest that the interaction is not clinically relevant; however, patients should be monitored for opiate withdrawal symptoms. |
|
|
|
|
|
|
|
|
|
|
|
Proton pump inhibitors can be administered at the same time as a dose of LEXIVA with no change in plasma amprenavir concentrations. |
|
|
↑Tricyclics | Therapeutic concentration monitoring is recommended for tricyclic antidepressants. |
|
|
|
|
|
Avoid atorvastatin
|
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
|
|
Do not exceed 20 mg atorvastatin daily
|
| HIV protease inhibitor (nelfinavir) | Do not exceed 40 mg atorvastatin daily |
| Table 5 Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours in healthy adult subjects (n=24) | ||
|
|
(Peak plasma concentration) |
(Extent of systemic exposure) |
| Erythromycin (500 mg every 8 hrs) |
+82% | +109% |
| Ketoconazole (400 mg once daily) |
+135% | +164% |
| Concomitant Drug Class: Drug Name | Effect | Clinical Comment |
|---|---|---|
|
|
||
| Protease inhibitor: atazanavir |
↓atazanavir concentration ↑ tenofovir concentration |
Coadministration of atazanavir with ATRIPLA is not recommended. Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA. |
| Protease inhibitor: fosamprenavir calcium |
↓ amprenavir concentration | Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and ATRIPLA with respect to safety and efficacy have not been established. Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when ATRIPLA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when ATRIPLA is administered with fosamprenavir plus ritonavir twice daily. |
| Protease inhibitor: indinavir |
↓ indinavir concentration | The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz. |
| Protease inhibitor: lopinavir/ritonavir |
↓ lopinavir concentration ↑ tenofovir concentration |
A dose increase of lopinavir/ritonavir to 600/150 mg (3 tablets) twice daily may be considered when used in combination with efavirenz in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). |
| Protease inhibitor: ritonavir |
↑ ritonavir concentration ↑ efavirenz concentration |
When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when ATRIPLA is used in combination with ritonavir. |
| Protease inhibitor: saquinavir |
↓ saquinavir concentration | Should not be used as sole protease inhibitor in combination with ATRIPLA. |
| CCR5 co-receptor antagonist: maraviroc |
↓ maraviroc concentration | Efavirenz decreases plasma concentrations of maraviroc. Refer to the full prescribing information for maraviroc for guidance on coadministration with ATRIPLA. |
| NRTI: didanosine |
↑ didanosine concentration | Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis and neuropathy. |
|
|
||
| Anticoagulant: warfarin |
↑ or ↓ warfarin concentration | Plasma concentrations and effects potentially increased or decreased by efavirenz. |
| Anticonvulsants: carbamazepine |
↓ carbamazepine concentration ↓ efavirenz concentration |
There are insufficient data to make a dose recommendation for ATRIPLA. Alternative anticonvulsant treatment should be used. |
| phenytoin phenobarbital |
↓ anticonvulsant concentration ↓ efavirenz concentration |
Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted. |
| Antidepressants: bupropion |
↓ buproprion concentration | The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded. |
| sertraline | ↓ sertraline concentration | Increases in sertraline dose should be guided by clinical response. |
| Antifungals: itraconazole |
↓ itraconazole concentration ↓ hydroxy-itraconazole concentration |
Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered. |
| ketoconazole | ↓ ketoconazole concentration | Drug interaction trials with ATRIPLA and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole. |
| posaconazole | ↓ posaconazole concentration | Avoid concomitant use unless the benefit outweighs the risks. |
| Anti-infective: clarithromycin |
↓ clarithromycin concentration ↑ 14-OH metabolite concentration |
Clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of ATRIPLA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with ATRIPLA. |
| Antimycobacterial: rifabutin |
↓ rifabutin concentration | Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week. |
| Antimycobacterial: rifampin |
↓ efavirenz concentration | If ATRIPLA is coadministered with rifampin to patients weighing 50 kg or more, an additional 200 mg/day of efavirenz is recommended. |
| Calcium channel blockers: diltiazem |
↓ diltiazem concentration ↓ desacetyl diltiazem concentration ↓ N-monodes-methyl diltiazem concentration |
Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of ATRIPLA is necessary when administered with diltiazem. |
| Others (e.g., felodipine, nicardipine, nifedipine, verapamil) |
↓ calcium channel blocker | No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker). |
| HMG-CoA reductase inhibitors: atorvastatin pravastatin simvastatin |
↓ atorvastatin concentration ↓ pravastatin concentration ↓ simvastatin concentration |
Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose. |
| Hormonal contraceptives: | ||
| Oral: ethinyl estradiol/norgestimate |
↓ active metabolites of norgestimate | A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed. |
| Implant: etonogestrel |
↓ etonogestrel | A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients. |
| Immunosuppressants: cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A |
↓ immuno-suppressant | Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by efavirenz. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with ATRIPLA. |
| Narcotic analgesic: methadone |
↓ methadone concentration | Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms. |
| Interacting Agents | Prescribing Recommendations |
|---|---|
| Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin |
| Amiodarone, verapamil, diltiazem |
Do not exceed 10 mg simvastatin daily |
| Amlodipine, ranolazine |
Do not exceed 20 mg simvastatin daily |
| Grapefruit juice |
Avoid large quantities of grapefruit juice (>1 quart daily) |
|
|
|
(mg) |
|
Pharmacokinetic Parameters (90% CI); No Effect = 1.00 |
||
| Cmax | AUC | Cmin | ||||
| All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated. | ||||||
| Cimetidine | 600 twice daily, 6 days |
400 single dose | 12 | 1.07 (0.77, 1.49) |
0.98 (0.81, 1.19) |
0.82 (0.69, 0.99) |
| Clarithromycin | 500 q12h, 7 days |
800 three times daily, 7 days |
10 | 1.08 (0.85, 1.38) |
1.19 (1.00, 1.42) |
1.57 (1.16, 2.12) |
| Delavirdine | 400 three times daily | 400 three times daily, 7 days |
28 | 0.64 (0.48, 0.86) |
No significant change |
2.18 (1.16, 4.12) |
| Delavirdine | 400 three times daily | 600 three times daily, 7 days |
28 | No significant change | 1.53 (1.07, 2.20) |
3.98 (2.04, 7.78) |
| Efavirenz |
600 once daily, 10 days |
1000 three times daily, 10 days |
20 | |||
| After morning dose | No significant change |
0.67 (0.61, 0.74) |
0.61 (0.49, 0.76) |
|||
| After afternoon dose | No significant change |
0.63 (0.54, 0.74) |
0.48 (0.43, 0.53) |
|||
| After evening dose | 0.71 (0.57, 0.89) |
0.54 (0.46, 0.63) |
0.43 (0.37, 0.50) |
|||
| Fluconazole |
400 once daily, 8 days |
1000 three times daily, 7 days | 11 | 0.87 (0.72, 1.05) |
0.76 (0.59, 0.98) |
0.90 (0.72, 1.12) |
| Grapefruit Juice | 8 oz. | 400 single dose | 10 | 0.65 (0.53, 0.79) |
0.73 (0.60, 0.87) |
0.90 (0.71, 1.15) |
| Isoniazid | 300 once daily in the morning, 8 days |
800 three times daily, 7 days | 11 | 0.95 (0.88, 1.03) |
0.99 (0.87, 1.13) |
0.89 (0.75, 1.06) |
| Itraconazole | 200 twice daily, 7 days |
600 three times daily, 7 days |
12 | 0.78 (0.69, 0.88) |
0.99 (0.91, 1.06) |
1.49 (1.28, 1.74) |
| Ketoconazole | 400 once daily, 7 days |
600 three times daily, 7 days |
12 | 0.69 (0.61, 0.78) |
0.80 (0.74, 0.87) |
1.29 (1.11, 1.51) |
| 400 once daily, 7 days |
400 three times daily, 7 days |
12 | 0.42 (0.37, 0.47) |
0.44 (0.41, 0.48) |
0.73 (0.62, 0.85) |
|
| Methadone | 20-60 once daily in the morning, 8 days |
800 three times daily, 8 days |
10 | See text below for discussion of interaction. | ||
| Quinidine | 200 single dose | 400 single dose | 10 | 0.96 (0.79, 1.18) |
1.07 (0.89, 1.28) |
0.93 (0.73, 1.19) |
| Rifabutin | 150 once daily in the morning, 10 days |
800 three times daily, 10 days |
14 | 0.80 (0.72, 0.89) |
0.68 (0.60, 0.76) |
0.60 (0.51, 0.72) |
| Rifabutin | 300 once daily in the morning, 10 days |
800 three times daily, 10 days |
10 | 0.75 (0.61, 0.91) |
0.66 (0.56, 0.77) |
0.61 (0.50, 0.75) |
| Rifampin | 600 once daily in the morning, 8 days |
800 three times daily, 7 days |
12 | 0.13 (0.08, 0.22) |
0.08 (0.06, 0.11) |
Not Done |
| Ritonavir | 100 twice daily, 14 days |
800 twice daily, 14 days |
10, 16 |
See text below for discussion of interaction. | ||
| Ritonavir | 200 twice daily, 14 days |
800 twice daily,14 days |
9, 16 |
See text below for discussion of interaction. | ||
| Sildenafil | 25 single dose | 800 three times daily | 6 | See text below for discussion of interaction. | ||
| St. John's wort ( standardized to 0.3 % hypericin) |
300 three times daily with meals, 14 days |
800 three times daily | 8 | Not Available | 0.46 (0.34, 0.58) |
0.19 (0.06, 0.33) |
| Stavudine (d4T) |
40 twice daily, 7 days |
800 three times daily, 7 days |
11 | 0.95 (0.80, 1.11) |
0.95 (0.80, 1.12) |
1.13 (0.83, 1.53) |
| Trimethoprim/ Sulfamethoxazole |
800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days |
400 four times daily, 7 days |
12 | 1.12 (0.87, 1.46) |
0.98 (0.81, 1.18) |
0.83 (0.72, 0.95) |
| Zidovudine |
200 three times daily, 7 days | 1000 three times daily, 7 days |
12 | 1.06 (0.91, 1.25) |
1.05 (0.86, 1.28) |
1.02 (0.77, 1.35) |
| Zidovudine/ Lamivudine (3TC) |
200/150 three times daily, 7 days |
800 three times daily, 7 days |
6, 9 |
1.05 (0.83, 1.33) |
1.04 (0.67, 1.61) |
0.98 (0.56, 1.73) |
|
|
|
|
|
Pharmacokinetic Parameters (90% CI); No Effect = 1.00 |
||
| Cmax | AUC | Cmin | ||||
| All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated. | ||||||
| Clarithromycin | 500 twice daily, 7 days |
800 three times daily, 7 days | 12 | 1.19 (1.02, 1.39) |
1.47 (1.30, 1.65) |
1.97 (1.58, 2.46) n=11 |
| Efavirenz | 200 once daily, 14 days |
800 three times daily, 14 days | 20 | No significant change | No significant change | -- |
| Ethinyl Estradiol (ORTHO-NOVUM 1/35) |
35 mcg, 8 days | 800 three times daily, 8 days | 18 | 1.02 (0.96, 1.09) |
1.22 (1.15, 1.30) |
1.37 (1.24, 1.51) |
| Isoniazid | 300 once daily in the morning, 8 days |
800 three times daily, 8 days | 11 | 1.34 (1.12, 1.60) |
1.12 (1.03, 1.22) |
1.00 (0.92, 1.08) |
| Methadone |
20-60 once daily in the morning, 8 days |
800 three times daily, 8 days | 12 | 0.93 (0.84, 1.03) |
0.96 (0.86, 1.06) |
1.06 (0.94, 1.19) |
| Norethindrone (ORTHO-NOVUM 1/35) |
1 mcg, 8 days | 800 three times daily, 8 days | 18 | 1.05 (0.95, 1.16) |
1.26 (1.20, 1.31) |
1.44 (1.32, 1.57) |
| Rifabutin •150 mg once daily in the morning, 11 days + indinavir compared to 300 mg once daily in the morning, 11 days alone |
150 once daily in the morning, 10 days 300 once daily in the morning, 10 days |
800 three times daily, 10 days 800 three times daily, 10 days |
14 10 |
1.29 (1.05, 1.59) 2.34 (1.64, 3.35) |
1.54 (1.33, 1.79) 2.73 (1.99, 3.77) |
1.99 (1.71, 2.31) n=13 3.44 (2.65, 4.46) n=9 |
| Ritonavir | 100 twice daily, 14 days |
800 twice daily, 14 days |
10, 4 |
1.61 (1.13, 2.29) |
1.72 (1.20, 2.48) |
1.62 (0.93, 2.85) |
| 200 twice daily, 14 days |
800 twice daily, 14 days |
9, 5 |
1.19 (0.85, 1.66) |
1.96 (1.39, 2.76) |
4.71 (2.66, 8.33) n=9, 4 |
|
| Saquinavir | ||||||
| Hard gel formulation | 600 single dose | 800 three times daily, 2 days | 6 | 4.7 (2.7, 8.1) |
6.0 (4.0, 9.1) |
2.9 (1.7, 4.7) |
| Soft gel formulation | 800 single dose | 800 three times daily, 2 days | 6 | 6.5 (4.7, 9.1) |
7.2 (4.3, 11.9) |
5.5 (2.2, 14.1) |
| Soft gel formulation | 1200 single dose | 800 three times daily, 2 days | 6 | 4.0 (2.7, 5.9) |
4.6 (3.2, 6.7) |
5.5 (3.7, 8.3) |
| Sildenafil | 25 single dose | 800 three times daily | 6 | See text below for discussion of interaction. | ||
| Stavudine |
40 twice daily, 7 days |
800 three times daily, 7 days | 13 | 0.86 (0.73, 1.03) |
1.21 (1.09, 1.33) |
Not Done |
| Theophylline | 250 single dose (on Days 1 and 7) | 800 three times daily, 6 days (Days 2 to 7) | 12, 4 |
0.88 (0.76, 1.03) |
1.14 (1.04, 1.24) |
1.13 (0.86, 1.49) n=7, 3 |
| Trimethoprim/ Sulfamethoxazole |
||||||
| Trimethoprim | 800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days |
400 q6h, 7 days | 12 | 1.18 (1.05, 1.32) |
1.18 (1.05, 1.33) |
1.18 (1.00, 1.39) |
| Trimethoprim/ Sulfamethoxazole |
||||||
| Sulfamethoxazole | 800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days |
400 q6h, 7 days | 12 | 1.01 (0.95, 1.08) |
1.05 (1.01, 1.09) |
1.05 (0.97, 1.14) |
| Vardenafil | 10 single dose | 800 three times daily | 18 | See text below for discussion of interaction. | ||
| Zidovudine |
200 three times daily, 7 days | 1000 three times daily, 7 days | 12 | 0.89 (0.73, 1.09) |
1.17 (1.07, 1.29) |
1.51 (0.71, 3.20) n=4 |
| Zidovudine/ Lamivudine |
||||||
| Zidovudine | 200/150 three times daily, 7 days | 800 three times daily, 7 days | 6, 7 |
1.23 (0.74, 2.03) |
1.39 (1.02, 1.89) |
1.08 (0.77, 1.50) n=5, 5 |
| Zidovudine/ Lamivudine |
||||||
| Lamivudine | 200/150 three times daily, 7 days | 800 three times daily, 7 days | 6, 7 |
0.73 (0.52, 1.02) |
0.91 (0.66, 1.26) |
0.88 (0.59, 1.33) |
| Coadministered Drug |
Dosing Schedule |
|
Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
|
Risperidone Dose Recommendation |
|
|
Coadministered Drug |
Risperidone |
AUC |
Cm
a
x
|
|
| Enzyme (CYP2D6) Inhibitors |
|
|
|
|
|
| Fluoxetine |
20 mg/day |
2 or 3 mg twice daily |
1.4 |
1.5 |
Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine |
10 mg/day |
4 mg/day |
1.3 |
- |
Re-evaluate dosing. |
|
|
20 mg/day |
4 mg/day |
1.6 |
- |
Do not exceed 8 mg/day |
|
|
40 mg/day |
4 mg/day |
1.8 |
- |
|
| Enzyme (CYP3A/ PgP inducers) |
|
|
|
|
|
| Carbamazepine |
573 ± 168 mg/day |
3 mg twice daily |
0.51 |
0.55 |
Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors |
|
|
|
|
|
| Ranitidine |
150 mg twice daily |
1 mg single dose |
1.2 |
1.4 |
Dose adjustment not needed |
| Cimetidine |
400 mg twice daily |
1 mg single dose |
1.1 |
1.3 |
Dose adjustment not needed |
| Erythromycin |
500 mg four times daily |
1 mg single dose |
1.1 |
0.94 |
Dose adjustment not needed |
| Other Drugs |
|
|
|
|
|
| Amitriptyline |
50 mg twice daily |
3 mg twice daily |
1.2 |
1.1 |
Dose adjustment not needed |
|
|
|
|
|
||
|
|
|||
| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
|
|
|||
|
|
|||
| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
|
|
|||
|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
| |
|||
|
|
|
||
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
||
|
|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
| |
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| |
|||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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|
|||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
|
|
|||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
|
|
|||
| Digoxin Serum Concentration Increase |
Digoxin AUC Increase |
|
|
| Amiodarone | 70% | NA | Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30% to 50% or by modifying the dosing frequency and continue monitoring. |
| Captopril | 58% | 39% | |
| Clarithromycin | NA | 70% | |
| Dronedarone | NA | 150% | |
| Gentamicin | 129-212% | NA | |
| Erythromycin | 100% | NA | |
| Itraconazole | 80% | NA | |
| Nitrendipine | 57% | 15% | |
| Propafenone | NA | 60-270% | |
| Quinidine | 100% | NA | |
| Ranolazine | 50% | NA | |
| Ritonavir | NA | 86% | |
| Tetracycline | 100% | NA | |
| Verapamil | 50-75% | NA | |
|
|
|||
| Atorvastatin | 22% | 15% | Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15% to 30% or by modifying the dosing frequency and continue monitoring. |
| Carvedilol | 16% | 14% | |
| Diltiazem | 20% | NA | |
| Indomethacin | 40% | NA | |
| Nefazodone | 27% | 15% | |
| Nifedipine | 45% | NA | |
| Propantheline | 24% | 24% | |
| Quinine | NA | 33% | |
| Saquinavir | 27% | 49% | |
| Spironolactone | 25% | NA | |
| Telmisartan | 20-49% | NA | |
| Tolvaptan | 30% | NA | |
| Trimethoprim | 22-28% | NA | |
|
|
|||
| Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole, quinine, rabeprazole, |
Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary. | ||
|
|
|||
| Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate, sulfasalazine |
Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20 % to 40 % as necessary. | ||
|
|
|||
| Please refer to section 12 for a complete list of drugs which were studies but reported no significant changes on digoxin exposure. |
No additional actions are required. | ||
| NA – Not available/reported |
| Drugs that Affect Renal Function | Caution should be exercised when combining digoxin with any drug that may cause significant deterioration in renal function (e.g., ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDs], COX-2 inhibitors) since a decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. | |
| Antiarrthymics | Dofetilide | Concomitant administration with digoxin was associated with a higher rate of torsades de pointes |
| Sotalol | Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin. | |
| Dronedarone | Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin. | |
| Parathyroid Hormone Analog | Teriparatide | Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium. |
| Thyroid supplement | Thyroid | Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin. |
| Sympathomimetics | Epinephrine Norepinephrine Dopamine |
Can increase the risk of cardiac arrhythmias |
| Neuromuscular Blocking Agents | Succinylcholine | May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin. |
| Supplements | Calcium | If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients. |
| Beta-adrenergic blockers and calcium channel blockers | Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block. |
|
Specific Drugs |
|
|
|---|---|---|
|
a For magnitude of interactions see |
||
|
b See |
||
| c In combination with atazanavir 300 mg and ritonavir 100 mg once daily. | ||
| d In combination with atazanavir 400 mg once daily. | ||
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|
||
|
didanosine buffered formulations enteric-coated (EC) capsules |
↓ atazanavir ↓ didanosine |
Coadministration of REYATAZ with didanosine buffered tablets resulted in a marked decrease in atazanavir exposure. It is recommended that REYATAZ be given (with food) 2 h before or 1 h after didanosine buffered formulations. Simultaneous administration of didanosine EC and REYATAZ with food results in a decrease in didanosine exposure. Thus, REYATAZ and didanosine EC should be administered at different times. |
|
|
↓ atazanavir ↑ tenofovir |
Tenofovir may decrease the AUC and Cmin of atazanavir. When coadministered with tenofovir, it is recommended that REYATAZ 300 mg be given with ritonavir 100 mg and tenofovir 300 mg (all as a single daily dose with food). |
|
|
↓ atazanavir | Efavirenz decreases atazanavir exposure. If REYATAZ is combined with efavirenz, REYATAZ 400 mg (two 200-mg capsules) with ritonavir 100 mg should be administered once daily all as a single dose with food, and efavirenz 600 mg should be administered once daily on an empty stomach, preferably at bedtime. Do not coadminister REYATAZ with efavirenz in treatment-experienced patients due to decreased atazanavir exposure. |
|
|
↓ atazanavir ↑ nevirapine |
Do not coadminister REYATAZ with
nevirapine because:
|
|
|
↑ saquinavir | Appropriate dosing recommendations for this combination, with or without ritonavir, with respect to efficacy and safety have not been established. In a clinical study, saquinavir 1200 mg coadministered with REYATAZ 400 mg and tenofovir 300 mg (all given once daily) plus nucleoside analogue reverse transcriptase inhibitors did not provide adequate efficacy [see |
|
|
↑ atazanavir | If REYATAZ is coadministered with ritonavir, it is recommended that REYATAZ 300 mg once daily be given with ritonavir 100 mg once daily with food. See the complete prescribing information for NORVIR® (ritonavir) for information on drug interactions with ritonavir. |
|
|
↑ other protease inhibitor |
|
|
|
||
|
|
↓ atazanavir | Reduced plasma concentrations of atazanavir are expected if antacids, including buffered medications, are administered with REYATAZ. REYATAZ should be administered 2 hours before or 1 hour after these medications. |
|
|
↑ amiodarone, bepridil, lidocaine (systemic), quinidine | Coadministration with REYATAZ has the potential to produce serious and/or life-threatening adverse events and has not been studied. Caution is warranted and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ (atazanavir sulfate). |
|
|
↑ warfarin | Coadministration with REYATAZ has the potential to produce serious and/or life-threatening bleeding and has not been studied. It is recommended that INR (International Normalized Ratio) be monitored. |
|
|
↑ tricyclic antidepressants | Coadministration with REYATAZ has the potential to produce serious and/or life-threatening adverse events and has not been studied. Concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ. |
| trazodone | ↑ trazodone | Concomitant use of trazodone and REYATAZ with or without ritonavir may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as REYATAZ, the combination should be used with caution and a lower dose of trazodone should be considered. |
|
|
↑ ketoconazole ↑ itraconazole |
Coadministration of ketoconazole has only been studied with REYATAZ without ritonavir (negligible increase in atazanavir AUC and Cmax). Due to the effect of ritonavir on ketoconazole, high doses of ketoconazole and itraconazole (>200 mg/day) should be used cautiously with REYATAZ/ritonavir. |
|
|
Effect is unknown | Coadministration of voriconazole with REYATAZ, with or without ritonavir, has not been studied. Administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%. Voriconazole should not be administered to patients receiving REYATAZ/ritonavir, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Coadministration of voriconazole with REYATAZ (without ritonavir) may increase atazanavir concentrations; however, no data are available. |
|
|
↑ colchicine | REYATAZ should not be coadministered with colchicine to patients with renal or hepatic impairment. Treatment of gout flares:
|
|
|
↑ rifabutin | A rifabutin dose reduction of up to 75% (eg, 150 mg every other day or 3 times per week) is recommended. Increased monitoring for rifabutin-associated adverse reactions including neutropenia is warranted. |
|
|
↑ midazolam | Concomitant use of parenteral midazolam with REYATAZ may increase plasma concentrations of midazolam. Coadministration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Coadministration of oral midazolam with REYATAZ is CONTRAINDICATED. |
|
|
↑ diltiazem and desacetyl-diltiazem | Caution is warranted. A dose reduction of diltiazem by 50% should be considered. ECG monitoring is recommended. Coadministration of REYATAZ/ritonavir with diltiazem has not been studied. |
| eg, felodipine, nifedipine, nicardipine, and verapamil | ↑ calcium channel blocker | Caution is warranted. Dose titration of the calcium channel blocker should be considered. ECG monitoring is recommended. |
|
|
↓ atazanavir ↑ bosentan |
Plasma concentrations of atazanavir may be decreased when bosentan is administered with REYATAZ without ritonavir. Coadministration of bosentan and REYATAZ without ritonavir is not recommended.
|
|
|
↑ atorvastatin ↑ rosuvastatin |
Use the lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with REYATAZ (with or without ritonavir). The risk of myopathy, including rhabdomyolysis, may be increased when HIV protease inhibitors, including REYATAZ, are used in combination with these drugs. |
|
|
↓ atazanavir | Plasma concentrations of atazanavir were substantially decreased when REYATAZ 400 mg once daily was administered simultaneously with famotidine 40 mg twice daily, which may result in loss of therapeutic effect and development of resistance. |
|
REYATAZ 300 mg with ritonavir 100 mg once daily with food should be administered simultaneously with, and/or at least 10 hours after, a dose of the H2-receptor antagonist. An H2-receptor antagonist dose comparable to famotidine 20 mg once daily up to a dose comparable to famotidine 40 mg twice daily can be used with REYATAZ 300 mg with ritonavir 100 mg in treatment-naive patients. OR For patients unable to tolerate ritonavir, REYATAZ 400 mg once daily with food should be administered at least 2 hours before and at least 10 hours after a dose of the H2-receptor antagonist. No single dose of the H2-receptor antagonist should exceed a dose comparable to famotidine 20 mg, and the total daily dose should not exceed a dose comparable to famotidine 40 mg. However, REYATAZ should not be used without ritonavir in pregnant women. |
||
|
Whenever an H2-receptor antagonist is given to a patient receiving REYATAZ with ritonavir, the H2-receptor antagonist dose should not exceed a dose comparable to famotidine 20 mg twice daily, and the REYATAZ and ritonavir doses should be administered simultaneously with, and/or at least 10 hours after, the dose of the H2-receptor antagonist.
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|
↓ ethinyl estradiol ↑ norgestimatec ↑ ethinyl estradiol ↑ norethindroned |
Use with caution if coadministration of REYATAZ or REYATAZ/ritonavir with oral contraceptives is considered. If an oral contraceptive is administered with REYATAZ plus ritonavir, it is recommended that the oral contraceptive contain at least
35 mcg of ethinyl estradiol. If REYATAZ is administered without ritonavir, the oral contraceptive should contain no more than 30 mcg of ethinyl estradiol. Potential safety risks include substantial increases in progesterone exposure. The long-term effects of increases in concentration of the progestational agent are unknown and could increase the risk of insulin resistance, dyslipidemia, and acne. Coadministration of REYATAZ or REYATAZ/ritonavir with other hormonal contraceptives (eg, contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than norethindrone or norgestimate, or less than 25 mcg of ethinyl estradiol, has not been studied; therefore, alternative methods of contraception are recommended. |
|
|
↑ immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with REYATAZ (atazanavir sulfate). |
|
|
↑ salmeterol | Coadministration of salmeterol with REYATAZ is not recommended. Concomitant use of salmeterol and REYATAZ may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia. |
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|
|
Concomitant use of fluticasone propionate and REYATAZ (without ritonavir) may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use. |
|
|
Concomitant use of fluticasone propionate and REYATAZ/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression, have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Coadministration of fluticasone propionate and REYATAZ/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects [see |
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|
|
↑ clarithromycin ↓ 14-OH clarithromycin ↑ atazanavir |
Increased concentrations of clarithromycin may cause QTc prolongations; therefore, a dose reduction of clarithromycin by 50% should be considered when it is coadministered with REYATAZ. In addition, concentrations of the active metabolite 14-OH clarithromycin are significantly reduced; consider alternative therapy for indications other than infections due to |
|
|
↑ buprenorphine ↑ norbuprenorphine |
Coadministration of buprenorphine and REYATAZ with or without ritonavir increases the plasma concentration of buprenorphine and norbuprenorphine. Coadministration of REYATAZ plus ritonavir with buprenorphine warrants clinical monitoring for sedation and cognitive effects. A dose reduction of buprenorphine may be considered. Coadministration of buprenorphine and REYATAZ with ritonavir is not expected to decrease atazanavir plasma concentrations. Coadministration of buprenorphine and REYATAZ without ritonavir may decrease atazanavir plasma concentrations. REYATAZ without ritonavir should not be coadministered with buprenorphine. |
|
|
↑ sildenafil ↑ tadalafil ↑ vardenafil |
Coadministration with REYATAZ has not been studied but may result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism.
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↓ atazanavir | Plasma concentrations of atazanavir were substantially decreased when REYATAZ 400 mg or REYATAZ 300 mg/ritonavir 100 mg once daily was administered with omeprazole 40 mg once daily, which may result in loss of therapeutic effect and development of resistance. |
|
The proton-pump inhibitor dose should not exceed a dose comparable to omeprazole 20 mg and must be taken approximately 12 hours prior to the REYATAZ 300 mg with ritonavir 100 mg dose. |
||
|
Proton-pump inhibitors should not be used in treatment-experienced patients receiving REYATAZ. |
||
| Enzyme | Inhibitors | Inducers |
|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
| Drug Class | Specific Drugs |
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
| Interacting Agents | Prescribing Recommendations |
|---|---|
| Strong CYP3A4 inhibitors (e.g.,Itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone |
Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine |
Do not exceed 20 mg simvastatin daily |
| Grapefruit juice |
Avoid grapefruit juice |
| Concomitant Drug Class: Drug Name |
Effect on Concentration of Rilpivirine or Concomitant Drug |
Clinical Comment |
|---|---|---|
| ↑ = increase, ↓ = decrease, ↔ = no change |
||
|
|
||
| didanosine |
↔ rilpivirine ↔ didanosine |
No dose adjustment is required when EDURANT is co-administered with didanosine. Didanosine is to be administered on an empty stomach and at least two hours before or at least four hours after EDURANT (which should be administered with a meal). |
|
|
||
| NNRTI (delavirdine) |
↑ rilpivirine ↔ delavirdine |
It is not recommended to co-administer EDURANT with delavirdine and other NNRTIs. |
| Other NNRTIs (efavirenz, etravirine, nevirapine) |
↓ rilpivirine ↔ other NNRTIs |
|
|
|
||
| darunavir/ritonavir |
↑ rilpivirine ↔ boosted darunavir |
Concomitant use of EDURANT with darunavir/ritonavir may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when EDURANT is co-administered with darunavir/ritonavir. |
| lopinavir/ritonavir |
↑ rilpivirine ↔ boosted lopinavir |
Concomitant use of EDURANT with lopinavir/ritonavir may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when EDURANT is co-administered with lopinavir/ritonavir. |
| other boosted PIs (atazanavir/ritonavir, fosamprenavir/ritonavir, saquinavir/ritonavir, tipranavir/ritonavir) |
↑ rilpivirine ↔ boosted PI |
Concomitant use of EDURANT with boosted PIs may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). EDURANT is not expected to affect the plasma concentrations of co-administered PIs. |
| unboosted PIs (atazanavir, fosamprenavir, indinavir, nelfinavir) |
↑ rilpivirine ↔ unboosted PI |
Concomitant use of EDURANT with unboosted PIs may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). EDURANT is not expected to affect the plasma concentrations of co-administered PIs. |
|
|
||
|
antacids (e.g., aluminum or magnesium hydroxide, calcium carbonate) |
↔ rilpivirine (antacids taken at least 2 hours before or at least 4 hours after rilpivirine) |
The combination of EDURANT and antacids should be used with caution as co-administration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). Antacids should only be administered either at least 2 hours before or at least 4 hours after EDURANT. |
| ↓ rilpivirine (concomitant intake) |
||
|
fluconazole itraconazole ketoconazole posaconazole voriconazole |
↑ rilpivirine ↓ ketoconazole |
Concomitant use of EDURANT with azole antifungal agents may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No rilpivirine dose adjustment is required when EDURANT is co-administered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are co-administered with EDURANT. |
|
cimetidine famotidine nizatidine ranitidine |
↔ rilpivirine (famotidine taken 12 hours before rilpivirine or 4 hours after rilpivirine) |
The combination of EDURANT and H2-receptor antagonists should be used with caution as co-administration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). H2-receptor antagonists should only be administered at least 12 hours before or at least 4 hours after EDURANT. |
| ↓ rilpivirine (famotidine taken 2 hours before rilpivirine) |
||
|
clarithromycin erythromycin telithromycin |
↑ rilpivirine ↔ clarithromycin ↔ erythromycin ↔ telithromycin |
Concomitant use of EDURANT with clarithromycin, erythromycin or telithromycin may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Where possible, alternatives such as azithromycin should be considered. |
|
methadone |
↓ R(-) methadone ↓ S(+) methadone |
No dose adjustments are required when initiating co-administration of methadone with EDURANT. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients. |
| Enzyme | Inhibitors | Inducers |
|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
| Drug Class | Specific Drugs |
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
| Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) | VIAGRA 25 mg |
|---|---|
| Supine | 7.4 (-0.9, 15.7) |
| Standing | 6.0 (-0.8, 12.8) |
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| Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) | VIAGRA 100 mg |
|---|---|
| Supine | 7.9 (4.6, 11.1) |
| Standing |
4.3 (-1.8,10.3) |
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| Coadministered drug (Postulated effect on CYP450/UGT) | Dose schedules | Effect on asenapine pharmacokinetics | Recommendation | ||
|---|---|---|---|---|---|
| Coadministered drug | Asenapine | Cmax | AUC0–∞ | ||
| Fluvoxamine (CYP1A2 inhibitor) |
25 mg twice daily for 8 days | 5 mg Single Dose | +13% | +29% | Coadminister with caution |
| Paroxetine (CYP2D6 inhibitor) |
20 mg once daily for 9 days | 5 mg Single Dose | –13% | –9% | No SAPHRIS dose adjustment required |
| Imipramine (CYP1A2/2C19/3A4 inhibitor) | 75 mg Single Dose | 5 mg Single Dose | +17% | +10% | No SAPHRIS dose adjustment required |
| Cimetidine (CYP3A4/2D6/1A2 inhibitor) | 800 mg twice daily for 8 days | 5 mg Single Dose | –13% | +1% | No SAPHRIS dose adjustment required |
| Carbamazepine (CYP3A4 inducer) |
400 mg twice daily for 15 days | 5 mg Single Dose | –16% | –16% | No SAPHRIS dose adjustment required |
| Valproate (UGT1A4 inhibitor) |
500 mg twice daily for 9 days | 5 mg Single Dose | 2% | –1% | No SAPHRIS dose adjustment required |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine | Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide | ↓ lamotrigine | Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine | Increased lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
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| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid grapefruit juice |
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
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|---|---|---|
| * The interaction between SUSTIVA and the drug was evaluated in a clinical study. All other drug interactions shown are predicted. | ||
| This table is not all-inclusive. | ||
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| Protease inhibitor: Fosamprenavir calcium |
↓ amprenavir |
Fosamprenavir
(unboosted): Appropriate doses of the combinations with respect to safety
and efficacy have not been established. Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when SUSTIVA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when SUSTIVA is administered with fosamprenavir plus ritonavir twice daily. |
| Protease inhibitor: Atazanavir sulfate |
↓ atazanavir* |
|
| Protease inhibitor: Indinavir |
↓ indinavir* |
The optimal dose of indinavir, when given in combination with SUSTIVA, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to SUSTIVA. When indinavir at an increased dose (1000 mg every 8 hours) was given with SUSTIVA (600 mg once daily), the indinavir AUC and Cmin were decreased on average by 33-46% and 39-57%, respectively, compared to when indinavir (800 mg every 8 hours) was given alone. |
| Protease inhibitor: Lopinavir/ritonavir |
↓ lopinavir* |
Lopinavir/ritonavir tablets should not be administered once daily in combination with SUSTIVA. In antiretroviral-naive patients, lopinavir/ritonavir tablets can be used twice daily in combination with SUSTIVA with no dose adjustment. A dose increase of lopinavir/ritonavir tablets to 600/150 mg (3 tablets) twice daily may be considered when used in combination with SUSTIVA in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). A dose increase of lopinavir/ritonavir oral solution to 533/133 mg (6.5 mL) twice daily taken with food is recommended when used in combination with SUSTIVA. |
| Protease inhibitor: Ritonavir |
↑ ritonavir* ↑ efavirenz* |
When ritonavir 500 mg q12h was coadministered with SUSTIVA 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (eg, dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when SUSTIVA is used in combination with ritonavir. |
| Protease inhibitor: Saquinavir |
↓ saquinavir* |
Should not be used as sole protease inhibitor in combination with SUSTIVA. |
| NNRTI: Other NNRTIs |
↑ or ↓ efavirenz and/or NNRTI |
Combining two NNRTIs has not been shown to be beneficial. SUSTIVA should not be coadministered with other NNRTIs. |
| CCR5 co-receptor antagonist: Maraviroc |
↓ maraviroc* |
Refer to the full prescribing information for maraviroc for guidance on coadministration with efavirenz. |
| Integrase strand transfer inhibitor: Raltegravir |
↓ raltegravir* |
SUSTIVA reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed. |
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|
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| Protease inhibitor: Boceprevir |
↓ boceprevir* |
Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with SUSTIVA, which may result in loss of therapeutic effect. The combination should be avoided. |
| Protease inhibitor: Telaprevir |
↓ telaprevir* ↓ efavirenz* |
Concomitant administration of telaprevir and SUSTIVA resulted in reduced steady-state exposures to telaprevir and efavirenz. |
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|
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| Anticoagulant: Warfarin |
↑ or ↓ warfarin |
Plasma concentrations and effects potentially increased or decreased by SUSTIVA. |
| Anticonvulsants: Carbamazepine |
↓ carbamazepine* ↓ efavirenz* |
There are insufficient data to make a dose recommendation for efavirenz. Alternative anticonvulsant treatment should be used. |
| Phenytoin Phenobarbital |
↓ anticonvulsant ↓ efavirenz |
Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted. |
| Antidepressants: Bupropion |
↓ bupropion* |
The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded. |
| Sertraline | ↓ sertraline* | Increases in sertraline dosage should be guided by clinical response. |
| Antifungals: Voriconazole |
↓ voriconazole* ↑ efavirenz* |
SUSTIVA and voriconazole must not be coadministered at standard doses. Efavirenz significantly decreases voriconazole plasma concentrations, and coadministration may decrease the therapeutic effectiveness of voriconazole. Also, voriconazole significantly increases efavirenz plasma concentrations, which may increase the risk of SUSTIVA-associated side effects. When voriconazole is coadministered with SUSTIVA, voriconazole maintenance dose should be increased to 400 mg every 12 hours and SUSTIVA dose should be decreased to 300 mg once daily using the capsule formulation. SUSTIVA tablets should not be broken. [See |
|
Itraconazole |
↓ itraconazole* ↓ hydroxyitraconazole* |
Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered. |
| Ketoconazole | ↓ ketoconazole | Drug interaction studies with SUSTIVA and ketoconazole have not been conducted. SUSTIVA has the potential to decrease plasma concentrations of ketoconazole. |
| Posaconazole | ↓ posaconazole* | Avoid concomitant use unless the benefit outweighs the risks. |
| Anti-infective: Clarithromycin |
↓ clarithromycin* ↑ 14-OH metabolite* |
Plasma concentrations
decreased by SUSTIVA; clinical significance unknown. In uninfected volunteers,
46% developed rash while receiving SUSTIVA and clarithromycin. No dose adjustment
of SUSTIVA is recommended when given with clarithromycin. Alternatives to
clarithromycin, such as azithromycin, should be considered (see |
| Antimycobacterials: Rifabutin |
↓ rifabutin* |
Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week. |
| Rifampin | ↓ efavirenz* | If SUSTIVA is coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of SUSTIVA to 800 mg once daily is recommended. |
| Calcium channel blockers: Diltiazem |
↓ diltiazem* ↓ desacetyl diltiazem* ↓ N-monodesmethyl diltiazem* |
Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of efavirenz is necessary when administered with diltiazem. |
| Others (eg, felodipine, nicardipine, nifedipine, verapamil) |
↓ calcium channel blocker |
No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker). |
| HMG-CoA reductase
inhibitors: Atorvastatin Pravastatin Simvastatin |
↓ atorvastatin* ↓ pravastatin* ↓ simvastatin* |
Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose. |
| Hormonal contraceptives: Oral Ethinyl estradiol/ Norgestimate |
↓ active metabolites of norgestimate* |
A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed. |
| Implant Etonogestrel |
↓ etonogestrel |
A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients. |
| Immunosuppressants: Cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A |
↓ immunosuppressant |
Decreased exposure of the immunosuppressant may be expected due to CYP3A induction. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with efavirenz. |
| Narcotic analgesic: Methadone |
↓ methadone* |
Coadministration in HIV-infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms. |
| blood dyscrasias — | diarrhea | hyperthyroidism |
| see |
elevated temperature | poor nutritional state |
| cancer | hepatic disorders | steatorrhea |
| collagen vascular disease | infectious hepatitis | vitamin K deficiency |
| congestive heart failure | jaundice |
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| 5-lipoxygenase Inhibitor | Antiplatelet Drugs/Effects | Leukotriene Receptor Antagonist |
| Adrenergic Stimulants, Central | Antithyroid Drugs† | Monoamine Oxidase Inhibitors |
| Alcohol Abuse Reduction | Beta-Adrenergic Blockers | Narcotics, prolonged |
| Preparations | Cholelitholytic Agents | Nonsteroidal Anti- |
| Analgesics | Diabetes Agents, Oral | Inflammatory Agents |
| Anesthetics, Inhalation | Diuretics† | Proton Pump Inhibitors |
| Antiandrogen | Fungal Medications, | Psychostimulants |
| Antiarrhythmics† | Intravaginal, Systemic† | Pyrazolones |
| Antibiotics† | Gastric Acidity and Peptic | Salicylates |
| Aminoglycosides (oral) | Ulcer Agents† | Selective Serotonin |
| Cephalosporins, parenteral | Gastrointestinal | Reuptake Inhibitors |
| Macrolides | Prokinetic Agents | Steroids, Adrenocortical† |
| Miscellaneous | Ulcerative Colitis Agents | Steroids, Anabolic (17-Alkyl |
| Penicillins, intravenous, | Gout Treatment Agents | Testosterone Derivatives) |
| high dose | Hemorrheologic Agents | Thrombolytics |
| Quinolones (fluoroquinolones) | Hepatotoxic Drugs | Thyroid Drugs |
| Sulfonamides, long acting | Hyperglycemic Agents | Tuberculosis Agents† |
| Tetracyclines | Hypertensive Emergency Agents | Uricosuric Agents |
| Anticoagulants | Hypnotics† | Vaccines |
| Anticonvulsants† | Hypolipidemics† | Vitamins† |
| Antidepressants† | Bile Acid-Binding Resins† | |
| Antimalarial Agents | Fibric Acid Derivatives | |
| Antineoplastics† | HMG-CoA Reductase Inhibitors† | |
| Antiparasitic/Antimicrobials | ||
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| acetaminophen | fenoprofen | paroxetine |
| alcohol |
fluconazole | penicillin G, intravenous |
| allopurinol | fluorouracil | pentoxifylline |
| aminosalicylic acid | fluoxetine | phenylbutazone |
| amiodarone HCl | flutamide | phenytoin |
| argatroban | fluvastatin | piperacillin |
| aspirin | fluvoxamine | piroxicam |
| atenolol | gefitinib | pravastatin |
| atorvastatin |
gemfibrozil | prednisone |
| azithromycin | glucagon | propafenone |
| bivalirudin | halothane | propoxyphene |
| capecitabine | heparin | propranolol |
| cefamandole | ibuprofen | propylthiouracil |
| cefazolin | ifosfamide | quinidine |
| cefoperazone | indomethacin | quinine |
| cefotetan | influenza virus vaccine | rabeprazole |
| cefoxitin | itraconazole | ranitidine |
| ceftriaxone | ketoprofen | rofecoxib |
| celecoxib | ketorolac | sertraline |
| cerivastatin | lansoprazole | simvastatin |
| chenodiol | lepirudin | stanozolol |
| chloramphenicol | levamisole | streptokinase |
| chloral hydrate |
levofloxacin | sulfamethizole |
| chlorpropamide | levothyroxine | sulfamethoxazole |
| cholestyramine |
liothyronine | sulfinpyrazone |
| cimetidine | lovastatin | sulfisoxazole |
| ciprofloxacin | mefenamic acid | sulindac |
| cisapride | methimazole |
tamoxifen |
| clarithromycin | methyldopa | tetracycline |
| clofibrate | methylphenidate | thyroid |
| warfarin sodium overdose | methylsalicylate ointment (topical) | ticarcillin |
| cyclophosphamide |
metronidazole | ticlopidine |
| danazol | miconazole | tissue plasminogen |
| dextran | (intravaginal, oral, systemic) | activator (t-PA) |
| dextrothyroxine | moricizine hydrochloride |
tolbutamide |
| diazoxide | nalidixic acid | tramadol |
| diclofenac | naproxen | trimethoprim/sulfamethoxazole |
| dicumarol | neomycin | urokinase |
| diflunisal | norfloxacin | valdecoxib |
| disulfiram | ofloxacin | valproate |
| doxycycline | olsalazine | vitamin E |
| erythromycin | omeprazole | zafirlukast |
| esomeprazole | oxandrolone | zileuton |
| ethacrynic acid | oxaprozin | |
| ezetimibe | oxymetholone | |
| fenofibrate | pantoprazole | |
| edema | hypothyroidism |
| hereditary coumarin resistance | nephrotic syndrome |
| hyperlipemia |
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| Adrenal Cortical Steroid Inhibitors | Antipsychotic Medications | Hypolipidemics† |
| Antacids | Antithyroid Drugs† | Bile Acid-Binding Resins† |
| Antianxiety Agents Antiarrhythmics† |
Barbiturates Diuretics† |
HMG-CoA Reductase Inhibitors† |
| Anticonvulsants† | Enteral Nutritional Supplements | Immunosuppressives |
| Antidepressants† | Fungal Medications, Systemic† | Oral Contraceptives, |
| Antihistamines | Gastric Acidity and Peptic Ulcer Agents† | Estrogen Containing |
| Antineoplastics† | Hypnotics† | Selective Estrogen Receptor Modulators |
| Steroids, Adrenocortical† | ||
| Tuberculosis Agents†
Vitamins† |
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| alcohol |
warfarin sodium underdosage | phenytoin |
| aminoglutethimide | cyclophosphamide |
pravastatin |
| amobarbital | dicloxacillin | prednisone |
| atorvastatin |
ethchlorvynol | primidone |
| azathioprine | glutethimide | propylthiouracil |
| butabarbital | griseofulvin | raloxifene |
| butalbital | haloperidol | ranitidine |
| carbamazepine | meprobamate | rifampin |
| chloral hydrate |
6-mercaptopurine | secobarbital |
| chlordiazepoxide | methimazole |
spironolactone |
| chlorthalidone | moricizine hydrochloride |
sucralfate |
| cholestyramine |
nafcillin | trazodone |
| clozapine | paraldehyde | vitamin C (high dose) |
| corticotropin | pentobarbital | vitamin K |
| cortisone | phenobarbital | |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
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| Amiodarone Iodide (including iodine- containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
| albuterol, | famotidine | nizatidine |
| systemic and inhaled | felodipine | norfloxacin |
| amoxicillin | finasteride | ofloxacin |
| ampicillin, | hydrocortisone | omeprazole |
| with or without | isoflurane | prednisone, prednisolone |
| sulbactam | isoniazid | ranitidine |
| atenolol | isradipine | rifabutin |
| azithromycin | influenza vaccine | roxithromycin |
| caffeine, | ketoconazole | sorbitol |
| dietary digestion | lomefloxacin | (purgative doses do not |
| cefaclor | mebendazole | inhibit theophylline |
| co-trimoxazole | medroxyprogesterone | absorption) |
| (trimethoprim and | methylprednisolone | sucralfate |
| sulfamethoxazole) | metronidazole | terbutaline, systemic |
| diltiazem | metoprolol | terfenadine |
| dirithromycin | nadolol | tetracycline |
| enflurane | nifedipine | tocainide |
| Concomitant Drug Class: Drug Name | Effect | Clinical Comment |
|---|---|---|
|
|
||
| Protease inhibitor: atazanavir |
↓atazanavir concentration ↑ tenofovir concentration |
Coadministration of atazanavir with ATRIPLA is not recommended. Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA. |
| Protease inhibitor: fosamprenavir calcium |
↓ amprenavir concentration | Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and ATRIPLA with respect to safety and efficacy have not been established. Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when ATRIPLA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when ATRIPLA is administered with fosamprenavir plus ritonavir twice daily. |
| Protease inhibitor: indinavir |
↓ indinavir concentration | The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz. |
| Protease inhibitor: lopinavir/ritonavir |
↓ lopinavir concentration ↑ tenofovir concentration |
A dose increase of lopinavir/ritonavir to 600/150 mg (3 tablets) twice daily may be considered when used in combination with efavirenz in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). |
| Protease inhibitor: ritonavir |
↑ ritonavir concentration ↑ efavirenz concentration |
When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when ATRIPLA is used in combination with ritonavir. |
| Protease inhibitor: saquinavir |
↓ saquinavir concentration | Should not be used as sole protease inhibitor in combination with ATRIPLA. |
| NRTI: didanosine |
↑ didanosine concentration | Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis and neuropathy. |
|
|
||
| Anticoagulant: warfarin |
↑ or ↓ warfarin concentration | Plasma concentrations and effects potentially increased or decreased by efavirenz. |
| Anticonvulsants: carbamazepine |
↓ carbamazepine concentration ↓ efavirenz concentration |
There are insufficient data to make a dose recommendation for ATRIPLA. Alternative anticonvulsant treatment should be used. |
| phenytoin phenobarbital |
↓ anticonvulsant concentration ↓ efavirenz concentration |
Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted. |
| Antidepressant: sertraline |
↓ sertraline concentration | Increases in sertraline dose should be guided by clinical response. |
| Antifungals: itraconazole |
↓ itraconazole concentration ↓ hydroxy-itraconazole concentration |
Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered. |
| ketoconazole | ↓ ketoconazole concentration | Drug interaction studies with ATRIPLA and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole. |
| Anti-infective: clarithromycin |
↓ clarithromycin concentration ↑ 14-OH metabolite concentration |
Clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of ATRIPLA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with ATRIPLA. |
| Antimycobacterial: rifabutin |
↓ rifabutin concentration | Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week. |
| Antimycobacterial: rifampin |
↓ efavirenz concentration |
Clinical significance of reduced efavirenz concentration is unknown. Dosing recommendations for concomitant use of ATRIPLA and rifampin have not been established. |
| Calcium channel blockers: diltiazem |
↓ diltiazem concentration ↓ desacetyl diltiazem concentration ↓ N-monodes-methyl diltiazem concentration |
Diltiazem dose adjustments should be guided by clinical response (refer to the prescribing information for diltiazem). No dose adjustment of ATRIPLA is necessary when administered with diltiazem. |
| Others (e.g., felodipine, nicardipine, nifedipine, verapamil) | ↓ calcium channel blocker | No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the prescribing information for the calcium channel blocker). |
| HMG-CoA reductase inhibitors: atorvastatin pravastatin simvastatin |
↓ atorvastatin concentration ↓ pravastatin concentration ↓ simvastatin concentration |
Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz. Consult the prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose. |
| Hormonal contraceptives: | ||
| Oral: Ethinyl estradiol/Norgestimate |
↓ active metabolites of norgestimate | A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed. |
| Implant: Etonogestrel |
↓ etonogestrel | A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients. |
| Immunosuppressants: Cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A |
↓ immuno-suppressant | Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by efavirenz. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with ATRIPLA. |
| Narcotic analgesic: methadone |
↓ methadone concentration | Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms. |
|
|
|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
|
Drug name |
|
|
|---|---|---|
| ↑ increase, ↓ decrease, ↔ no change, ↕ unable to predict | ||
|
HIV-1 Antiviral Agents |
||
|
|
||
| Enfuvirtide | ↑ Tipranavir | At steady state, tipranavir trough concentrations were approximately 45% higher in patients co-administered enfuvirtide in the Phase 3 trials. The mechanism for this increase is not known. Dose adjustments are not recommended. |
|
|
||
| Abacavir | ↓ Abacavir AUC by approximately 40% | Clinical relevance of reduction in abacavir levels not established. Dose adjustment of abacavir cannot be recommended at this time. |
| Didanosine (EC) | ↓ Didanosine | Clinical relevance of reduction in didanosine levels not established. For optimal absorption, didanosine should be separated from APTIVUS/ritonavir dosing by at least 2 hours. |
| Zidovudine | ↓ Zidovudine AUC by approximately 35%. ZDV glucuronide concentrations were unaltered. | Clinical relevance of reduction in zidovudine levels not established. Dose adjustment of zidovudine cannot be recommended at this time. |
|
|
||
| Fosamprenavir Lopinavir Saquinavir |
↓ Amprenavir ↓ Lopinavir ↓ Saquinavir |
Combining a protease inhibitor with APTIVUS/ritonavir is not recommended. |
|
|
||
| Atazanavir | ↓ Atazanavir ↑ Tipranavir |
|
|
|
||
| Raltegravir | ↓ Raltegravir | APTIVUS/ritonavir reduces plasma concentrations of raltegravir. Since comparable efficacy was observed for this combination in phase 3 studies, dose adjustment is not recommended. |
|
Agents for Opportunistic Infections |
||
|
|
||
| Fluconazole | ↑ Tipranavir, ↔ Fluconazole | Fluconazole increases tipranavir concentrations but dose adjustments are not needed. Fluconazole doses >200 mg/day are not recommended. |
| Itraconazole Ketoconazole |
↑ Itraconazole (not studied) ↑ Ketoconazole (not studied) |
Based on theoretical considerations itraconazole and ketoconazole should be used with caution. High doses (>200 mg/day) are not recommended. |
| Voriconazole | ↕ Voriconazole (not studied) | Due to multiple enzymes involved with voriconazole metabolism, it is difficult to predict the interaction. |
|
|
||
| Clarithromycin | ↑ Tipranavir, ↑ Clarithromycin, ↓ 14-hydroxy-clarithromycin metabolite |
No dose adjustment of APTIVUS or clarithromycin for patients with normal renal function is necessary. |
For patients with renal impairment the following dosage adjustments should be considered:
|
||
| Rifabutin | Tipranavir not changed, ↑ Rifabutin ↑ Desacetyl-rifabutin |
Single dose study. Dosage reductions of rifabutin by 75% are recommended (e.g., 150 mg every other day). Increased monitoring for adverse events in patients receiving the combination is warranted. Further dosage reduction may be necessary. |
| Other Agents Commonly Used |
||
|
|
||
| Carbamazepine Phenobarbital Phenytoin |
↓ Tipranavir | Caution should be used when prescribing carbamazepine, phenobarbital and/or phenytoin. APTIVUS may be less effective due to decreased tipranavir plasma concentration in patients taking these agents concomitantly. |
| Valproic Acid | ↓ Valproic Acid | Caution should be used when prescribing valproic acid. Valproic acid may be less effective due to decreased valproic acid plasma concentration in patients taking APTIVUS concomitantly. |
|
Trazodone |
↑ Trazodone |
Concomitant use of trazodone and APTIVUS/ritonavir may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP 3A4 inhibitor such as APTIVUS/ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered. |
| Desipramine | Combination with APTIVUS/ritonavir not studied ↑ Desipramine |
Dosage reduction and concentration monitoring of desipramine is recommended. |
| Selective Serotonin-Reuptake Inhibitors: | Combination with APTIVUS/ritonavir not studied | Antidepressants have a wide therapeutic index, but doses may need to be adjusted upon initiation of APTIVUS/ritonavir therapy. |
| Fluoxetine Paroxetine Sertraline |
↑ Fluoxetine ↑ Paroxetine ↑ Sertraline |
|
|
Colchicine |
↑ Colchicine |
|
|
|
||
| Parenterally administered midazolam | ↑ Midazolam | Midazolam is extensively metabolized by CYP 3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, APTIVUS should not be given with orally administered midazolam [ |
| Buprenorphine/naloxone | ↔ Buprenorphine ↓ Tipranavir |
APTIVUS/ritonavir did not result in changes in the clinical efficacy of buprenorphine/naloxone. Compared to historical controls tipranavir Cmin was decreased approximately 40% with this combination. Dose adjustments cannot be recommended. |
|
Diltiazem Felodipine Nicardipine Nisoldipine Verapamil |
Combination with APTIVUS/ritonavir not studied. Cannot predict effect of TPV/ritonavir on calcium channel blockers that are dual substrates of CYP3A and P-gp due to conflicting effect of TPV/ritonavir on CYP3A and P-gp. ↕ Diltiazem ↑ Felodipine (CYP3A substrate but not P-gp substrate) ↕ Nicardipine ↕ Nisoldipine (CYP3A substrate but not clear whether it is a P-gp substrate) ↕ Verapamil |
Caution is warranted and clinical monitoring of patients is recommended. |
| Disulfiram/Metronidazole | Combination with TPV/ritonavir not studied | APTIVUS capsules contain alcohol that can produce disulfiram-like reactions when co-administered with disulfiram or other drugs which produce this reaction (e.g., metronidazole). |
|
|
|
|
|
Bosentan |
↑ Bosentan |
In patients who have been receiving APTIVUS/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of APTIVUS/ritonavir. After at least 10 days following the initiation of APTIVUS/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. |
|
|
||
| Atorvastatin Rosuvastatin |
↑ Atorvastatin ↓ Hydroxy-atorvastatin metabolites ↑ Rosuvastatin |
Avoid co-administration with atorvastatin. |
|
|
||
| Combination with APTIVUS/ritonavir not studied | Careful glucose monitoring is warranted. | |
| Glimepiride Glipizide Glyburide Pioglitazone |
↔ Glimepiride (CYP 2C9) ↔ Glipizide (CYP 2C9) ↔ Glyburide (CYP 2C9) ↕ Pioglitazone (CYP 2C8 and CYP 3A4) |
|
| Repaglinide | ↕ Repaglinide (CYP 2C8 and CYP 3A4) | |
| Tolbutamide | ↔ Tolbutamide (CYP 2C9) The effect of TPV/ritonavir on CYP 2C8 substrate is not known. |
|
|
|
||
| Combination with APTIVUS/ritonavir not studied. Cannot predict effect of TPV/ritonavir on immunosuppressants due to conflicting effect of TPV/ritonavir on CYP 3A and P-gp. | Increased frequency of monitoring of plasma levels of immunosuppressant drugs is recommended. | |
| Cyclosporine Sirolimus Tacrolimus |
↕ Cyclosporine ↕ Sirolimus ↕ Tacrolimus |
|
|
Salmeterol |
↑ Salmeterol |
Concurrent administration of APTIVUS/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia. |
|
|
||
| Fluticasone | ↑ Fluticasone | Concomitant use of fluticasone propionate and APTIVUS/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Co-administration of fluticasone propionate and APTIVUS/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. |
|
|
||
| Meperidine | Combinations with APTIVUS/ritonavir not studied ↓ Meperidine, ↑ Normeperidine |
Dosage increase and long-term use of meperidine are not recommended due to increased concentrations of the metabolite normeperidine which has both analgesic activity and CNS stimulant activity (e.g., seizures). |
| Methadone | ↓ Methadone ↓ S-Methadone, ↓ R-Methadone |
Dosage of methadone may need to be increased when co-administered with APTIVUS and 200 mg of ritonavir. |
|
|
||
| Ethinyl estradiol | ↓ Ethinyl estradiol concentrations by 50% | Alternative methods of nonhormonal contraception should be used when estrogen based oral contraceptives are co-administered with APTIVUS and 200 mg of ritonavir. Patients using estrogens as hormone replacement therapy should be clinically monitored for signs of estrogen deficiency. Women using estrogens may have an increased risk of non-serious rash. |
|
|
||
| Omeprazole | ↓ Omeprazole, ↔ Tipranavir | Dosage of omeprazole may need to be increased when co-administered with APTIVUS and ritonavir. |
|
|
||
| Only the combination of tadalafil with APTIVUS/ritonavir has been studied (at doses used for treatment of erectile dysfunction). |
Co-administration with APTIVUS/ritonavir may result in an increase in PDE-5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. | |
| Sildenafil | ↑ Sildenafil (not studied) |
|
| Tadalafil | ↑ Tadalafil with first dose APTIVUS/ritonavir ↔ Tadalafil at APTIVUS/ritonavir steady-state |
In patients receiving APTIVUS/ritonavir for at least one week, start Adcirca at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. |
| Vardenafil | ↑ Vardenafil (not studied) |
Avoid use of tadalafil (Adcirca) during the initiation of APTIVUS/ritonavir. Stop Adcirca at least 24 hours prior to starting APTIVUS/ritonavir. After at least one week following the initiation of APTIVUS/ritonavir, resume Adcirca at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Concomitant use of PDE-5 inhibitors with APTIVUS/ritonavir should be used with caution and in no case should the starting dose of:
|
| Warfarin | ↔ S-Warfarin | Frequent INR (international normalized ratio) monitoring upon initiation of APTIVUS/ritonavir therapy. |
| CONCOMITANT DRUG | CLINICAL EFFECT(S) |
|---|---|
| Amphetamines, cocaine, other sympathomimetic agents | Additive hypertension, tachycardia, possibly cardiotoxicity |
| Atropine, scopolamine, antihistamines, other anticholinergic agents | Additive or super-additive tachycardia, drowsiness |
| Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants | Additive tachycardia, hypertension, drowsiness |
| Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants | Additive drowsiness and CNS depression |
| Disulfiram | A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge |
| Fluoxetine | A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine × 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days |
| Antipyrine, barbiturates | Decreased clearance of these agents, presumably via competitive inhibition of metabolism |
| Theophylline | Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco |
| Drug/Drug Class (Mechanism of Interaction by the Drug) |
Voriconazole Plasma Exposure (Cmax and AUCτ after 200 mg q12h) |
Recommendations for Voriconazole Dosage Adjustment/Comments |
|---|---|---|
| Rifampin (CYP450 Induction) |
Significantly Reduced |
|
| Efavirenz (CYP450 Induction) |
Significantly Reduced | When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h |
| High-dose Ritonavir (400 mg q12h) |
Significantly Reduced |
|
| Low-dose Ritonavir (100 mg q12h) |
Reduced | Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole |
| Carbamazepine (CYP450 Induction) |
Not Studied |
|
| Long Acting Barbiturates (CYP450 Induction) |
Not Studied |
|
| Phenytoin (CYP450 Induction) |
Significantly Reduced | Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg) |
| St. John's Wort (CYP450 inducer; P-gp inducer) |
Significantly Reduced |
|
| Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition) |
Increased | Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives |
| Fluconazole |
Significantly Increased | Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole. |
| Other HIV Protease Inhibitors (CYP3A4 Inhibition) |
|
No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir |
|
|
Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors |
|
| Other NNRTIs (CYP3A4 Inhibition or CYP450 Induction) |
|
Frequent monitoring for adverse events and toxicity related to voriconazole |
| A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure) |
Careful assessment of voriconazole effectiveness |
| Drug/Drug Class (Mechanism of Interaction by Voriconazole) |
Drug Plasma Exposure (Cmax and AUCτ) |
Recommendations for Drug Dosage Adjustment/Comments |
|---|---|---|
| Sirolimus (CYP3A4 Inhibition) |
Significantly Increased |
|
| Rifabutin (CYP3A4 Inhibition) |
Significantly Increased |
|
| Efavirenz (CYP3A4 Inhibition) |
Significantly Increased | When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h |
| High-dose Ritonavir (400 mg q12h) |
No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ |
|
| Low-dose Ritonavir (100 mg q12h) |
Slight Decrease in Ritonavir Cmax and AUCτ | Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole |
| Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition) |
Not Studied |
|
| Ergot Alkaloids (CYP450 Inhibition) |
Not Studied |
|
| Cyclosporine (CYP3A4 Inhibition) |
AUCτ Significantly Increased; No Significant Effect on Cmax | When initiating therapy with VFEND in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary. |
| Methadone |
Increased | Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed |
| Fentanyl (CYP3A4 Inhibition) |
Increased | Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary [ |
| Alfentanil (CYP3A4 Inhibition) | Significantly Increased | Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [ |
| Oxycodone (CYP3A4 Inhibition) | Significantly Increased | Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary [ |
| NSAIDs (CYP2C9 Inhibition) |
Increased | Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [ |
| Tacrolimus (CYP3A4 Inhibition) |
Significantly Increased | When initiating therapy with VFEND in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary. |
| Phenytoin (CYP2C9 Inhibition) |
Significantly Increased | Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin. |
| Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition) |
Increased | Monitoring for adverse events related to oral contraceptives is recommended during coadministration. |
| Warfarin (CYP2C9 Inhibition) |
Prothrombin Time Significantly Increased | Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed. |
| Omeprazole (CYP2C19/3A4 Inhibition) |
Significantly Increased | When initiating therapy with VFEND in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors. |
| Other HIV Protease Inhibitors (CYP3A4 Inhibition) |
|
No dosage adjustment for indinavir when coadministered with VFEND |
|
(Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors | |
| Other NNRTIs (CYP3A4 Inhibition) |
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to NNRTI |
| Benzodiazepines (CYP3A4 Inhibition) |
(Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed. |
| HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition) |
(Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed. |
| Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition) |
(Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed. |
| Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition) |
Not Studied |
Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed. |
| Vinca Alkaloids (CYP3A4 Inhibition) |
Not Studied |
Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed. |
| Systemic exposure to these drugs is increased significantly by the addition of ketoconazole: Concomitant use with ketoconazole is |
|
|---|---|
| Alprazolam, midazolam, triazolam | HMG-CoA reductase inhibitors (lovastatin, simvastatin) |
| Cisapride | Nisoldipine |
| Dofetilide | Pimozide |
| Eplerenone | Quinidine |
| Ergot alkaloids (ergotamine, dihydroergotamine) | |
|
Careful monitoring, with possible adjustment in dosage, is recommended. |
|
| Alfentanil, fentanyl, sulfentanil | Indinavir, saquinavir |
| Amlodipine, felodipine, nicardipine, nifedipine | Methylprednisolone |
| Bosentan | Rifabutin |
| Buspirone | Sildenafil |
| Busulfan | Sirolimus (co-administration not recommended) |
| Carbamazepine | Tacrolimus |
| Cilostazol | Telithromycin |
| Cyclosporine | Tolterodine |
| Digoxin | Trimetrexate |
| Docetaxel, paclitaxel | Verapamil |
| Oral anti-coagulants | Vinca alkaloids (vincristine, - vinblastine, vinorelbine) |
| Systemic exposure to ketoconazole is reduced significantly by these drugs: Concomitant use with ketoconazole is not recommended. |
|
|---|---|
| * This list is not all-inclusive. | |
| Carbamazepine | Phenytoin |
| Gastric Acid Suppressants (antacids, antimuscarinics, histamine H2-blockers, proton pump inhibitors, sucralfate) | Rifampin, rifabutin, isoniazid |
| Nevirapine | |
|
Dose reduction of ketoconazole should be considered |
|
| Ritonavir | |
|
albuterol, systemic and inhaled |
mebendazole |
|
amoxicillin |
medroxyprogesterone |
|
ampicillin, with or without |
methylprednisolone |
|
sulbactam |
metronidazole |
|
atenolol |
metoprolol |
|
azithromycin |
nadolol |
|
caffeine, dietary ingestion |
nifedipine |
|
cefaclor |
nizatidine |
|
co-trimoxazole (trimethoprim and sulfamethoxazole) |
norfloxacin |
|
ofloxacin |
|
|
diltiazem |
omeprazole |
|
dirithromycin |
prednisone, prednisolone |
|
enflurane |
ranitidine |
|
famotidine |
rifabutin |
|
felodipine |
roxithromycin |
|
finasteride |
Sorbitol (purgative doses do not inhibit |
|
hydrocortisone |
theophylline absorption) |
|
isoflurane |
sucralfate |
|
isoniazid |
terbutaline, systemic |
|
isradipine |
terfenadine |
|
influenza vaccine |
tetracycline |
|
ketoconazole |
tocainide |
|
lomefloxacin |
|
| Drug | Didanosine Dosage | n | AUC of Didanosine (90% CI) | Cmax of Didanosine (90% CI) |
|
|
400 mg single dose fasting 2 h before tenofovir | 26 |
(31, 67%) |
(25, 76%) |
|
|
400 mg single dose with tenofovir and a light meal | 25 |
(44, 79%) |
(41, 89%) |
|
|
|
|
(6, 27%)d |
(-25, 3%)d (-32, -7%)e (-24, 4%)e |
|
mL/min. b tenofovir disporoxil fumarate. c 373 kcalories, 8.2 grams fat. d Compared with didanosine delayed-release capsules 250 mg administered alone under fasting coniditions. e Compared with didanosine delayed-release capsules 400 mg administered alone under |
||||
| ↔ Indicates no change, or mean increase or decrease of less than 10%. | ||||
|
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|
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|
|
|
750 mg single dose 800 mg single dose 200 mg single dose 300 mg once daily with a light meal 300 mg once daily with a light meal |
|
|
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|
|
||||
| Drug | Didanosine Dosage | n | AUC Didanosine (95% CI) | Cmax of Didanosine (95% CI) |
|
|
200 mg single dose | 2 | ↑312% | ↑232% |
| healthy volunteer, 300 mg/day for 7 days | 400 mg single dose | 14 | ↑113% | ↑69% |
|
|
200 mg q12h | 12 | ↑111% | NA |
|
|
200 mg single dose | 16, 10a | ↓57% | ↓66% |
|
|
250c or 400 mg once daily for 7 days | 14 | ↑44% (31, 59%)d | ↔28% (11, 48%)d |
|
|
||||
| ciprofloxacin, 750 mg q12h for 3 days, 2 h before didanosine | 200 mg q12h for 3 days | 8e | ↓16% | ↓28% |
| ininavir, 800 mg single dose simultaneous | 200 mg single dose | 16 |
|
|
| 1 h before didanosine | 200 mg single dose | 16 | ↓17% (-27, -7%)d | ↓13% (-28, 5%)d |
| ketoconazole, 200 mg/day for 4 days, 2 h before didanosine | 375 mg q12h for 4 days | 12e | ↔ | ↓12% |
| loperamide, 4 mg q6h for 1 day | 300 mg single dose | 12e | ↔ | ↓23% |
| metoclopramide, 10 mg single dose | 300 mg single dose | 12e | ↔ | ↑13% |
| ranitidine, 150 mg 2 h before didansine | 375 mg single dose | 12e | ↑14% | ↑13% |
| rifabutin, 300 or 600 mg/day for 12 days | 167 or 250 mg q12h for 12 days | 11 | ↑13% (-1, 27%) | ↑17% (-4, 38%) |
| ritonavir, 600 mg q12h for 4 days | 200 mg q12h for 4 days | 12 | ↓13% (0, 23%) | ↓16% (5, 26%) |
| stavudine, 40 mg q12h for 4 days | 100 mg q12h for 4 days | 10 | ↔ | ↔ |
| sulfamethoxazole, 1000 mg single dose | 200 mg single dose | 8e | ↔ | ↔ |
| trimethoprim, 200 mg single dose | 200 mg single dose | 8e | ↔ | ↑17% (-23, 77%) |
| zidovudine, 200 mg q7h for 3 days | 200 mg q12h for 3 days | 8e | ↔ | ↔ |
|
↓ indicates decrease ↔ indicates no change, or mean increase or decrease of <10%. a Parellel-group design; entries are subjects receiving combination and control regimens, respectively. b tenogovir disoproxil fumarate c patients <60 kg with creatinine clearance >60 mL/min. e HIV-infected patients N/A Not available |
||||
| No Clinically Significant Interaction Observed | ||||
| Drug | Didanosine Dosage | n | AUC of Coadministered Drug (95% CI) | Cmax of Coadministered Drug (95% CI) |
| dapsone, 100 mg single dose | 200 mg q12h for 14 days | 6a | ↔ | ↔ |
| delaviridine, 400 mg single dose simultaneous | 125 or 200 mg q12h | 12a | ↓32%b | ↓53%b |
| 1 hr before didanosine | 125 or 200 mg q12h | 12a | ↑20% | ↑18% |
| ganciclovir, 1000 mg q8h, 2h after didanosine | 200 mg q12h | 12a | ↓21% | NA |
| nelfinavir, 750 mg single dose, 1 h after didanosine | 200 mg single dose | 10a | ↑12% | ↔ |
| ranitidine, 150 mg single dose, 2 h before didanosine | 375 mg single dose | 12a | ↓16% | ↔ |
| ritonavir, 600 mg q12h for 4 days | 200 mg q12h for 4 days | 12 | ↔ | ↔ |
| stavudine, 40 mg q12h for 4 days | 100 mg q12h for 4 days | 10a | ↔ | ↑17% |
| sulfamethoxazole, 1000 mg single dose | 200 mg single dose | 8a | ↓11% (-17, -4%) | ↓12% (-28, 8%) |
| tenofovir,C 300 mg once daily 1 h after didanosine | 250d or 400 mg once daily for 7 days | 14 | ↔ | ↔ |
| trimethoprim, 200 mg single dose | 200 mg single dose | 8a | ↑10% (-9, 34%) | ↓22% (-59, 49%) |
| zidovudine, 200 mg q8h for 3 days | 200 mg q12h for 3 days | 6a | ↓10% (-27, 11%) | ↓16.5% (-53, 47%) |
|
aHIV-infected patients. bThis result is probably related to the bugger and is not expected to occur with didanosine delayed-release capsules. ctenofovir disoproxil fumarate. dpatients <60 kg with creatinine clearance >60 mL/min. |
||||
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|
||
| Atazanavir/Ritonavir* | ↓ Atazanavir ↑ Nevirapine |
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures. |
| Fosamprenavir* | ↓Amprenavir ↑Nevirapine |
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. |
| Fosamprenavir/Ritonavir* | ↓Amprenavir ↑Nevirapine |
No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied. |
| Indinavir* | ↓ Indinavir | The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established. |
| Lopinavir/Ritonavir* | ↓Lopinavir | Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. |
| Nelfinavir* | ↓Nelfinavir M8 Metabolite ↓Nelfinavir Cmin |
The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established. |
| Saquinavir/ritonavir | The interaction between nevirapine and saquinavir/ritonavir has not been evaluated | The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established. |
|
|
||
| Efavirenz* | ↓ Efavirenz |
The appropriate doses of these combinations with respect to safety and efficacy have not been established. |
|
Delavirdine Etravirine Rilpivirine |
Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial. |
|
|
|
||
|
Methadone* |
↓ Methadone |
Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. |
|
Amiodarone, disopyramide, lidocaine |
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
|
Clarithromycin* |
↓ Clarithromycin ↑ 14-OH clarithromycin |
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against |
| Rifabutin* |
↑Rifabutin |
Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. |
| Rifampin* |
↓ Nevirapine |
Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead. |
|
Carbamazepine, clonazepam, ethosuximide |
Plasma concentrations of nevirapine and the anticonvulsant may be decreased. |
Use with caution and monitor virologic response and levels of anticonvulsants. |
|
Fluconazole* |
↑Nevirapine |
Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events. |
| Ketoconazole* |
↓ Ketoconazole |
Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. |
| Itraconazole |
↓ Itraconazole |
Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug. |
|
Warfarin |
Plasma concentrations may be decreased. | Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended. |
|
Diltiazem, nifedipine, verapamil |
Plasma concentrations may be decreased. | Appropriate doses for these combinations have not been established. |
|
Cyclophosphamide |
Plasma concentrations may be increased. | Appropriate doses for this combination have not been established. |
|
Ergotamine |
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
|
Cyclosporine, tacrolimus, sirolimus |
Plasma concentrations may be decreased. | Appropriate doses for these combinations have not been established. |
|
Cisapride |
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
|
Fentanyl |
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
|
Ethinyl estradiol and Norethindrone* |
↓ Ethinyl estradiol ↓ Norethindrone |
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended. |
| Concomitant Drug Class: Drug Name |
Effect on Concentration of Saquinavir or Concomitant Drug | Clinical Comment |
|---|---|---|
|
|
||
|
Delavirdine |
↑ Saquinavir Effect on delavirdine is not well established |
Appropriate doses of the combination with respect to safety and efficacy have not been established. |
|
Efavirenz nevirapine |
↓ Saquinavir ↔ Efavirenz |
Appropriate doses of the combination of efavirenz or nevirapine and INVIRASE/ritonavir with respect to safety and efficacy have not been established. |
|
Atazanavir |
↑ Saquinavir ↑ Ritonavir ↔ Atazanavir |
Atazanavir in combination with INVIRASE/ritonavir should be used with caution. Additive effects on PR interval prolongation may occur with INVIRASE/ritonavir |
|
Indinavir |
↑ Saquinavir Effect on indinavir is not well established |
Appropriate doses of the combination of indinavir and INVIRASE/ritonavir with respect to safety and efficacy have not been established. |
|
Lopinavir/ritonavir |
↔ Saquinavir ↔ Lopinavir ↓ Ritonavir |
Evidence from several clinical trials indicates that saquinavir concentrations achieved with the saquinavir and lopinavir/ritonavir combination are similar to those achieved following saquinavir/ritonavir 1000/100 mg. The recommended dose for this combination is saquinavir 1000 mg plus lopinavir/ritonavir 400/100 mg bid. Lopinavir/ritonavir in combination with INVIRASE should be used with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE |
|
Tipranavir/ritonavir |
↓ Saquinavir |
Combining saquinavir with tipranavir/ritonavir is not recommended. |
|
Enfuvirtide |
Saquinavir soft gel capsules/ritonavir ↔ enfuvirtide |
No clinically significant interaction was noted from a study in 12 HIV-1 subjects who received enfuvirtide concomitantly with saquinavir soft gel capsules/ritonavir 1000/100 mg bid. No dose adjustments are required. |
|
Maraviroc |
↑ Maraviroc | Maraviroc dose should be 150 mg twice daily when coadministered with INVIRASE/ritonavir. For further details see complete prescribing information for Selzentry® (maraviroc). |
|
|
||
| Ibutilide Sotalol |
Use with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE/ritonavir |
|
|
Warfarin |
↑ Warfarin | Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored. |
|
Carbamazepine |
↓ Saquinavir Effect on carbamazepine, phenobarbital, and phenytoin is not well established |
Use with caution. Saquinavir may be less effective due to decreased saquinavir plasma concentrations in patients taking these agents concomitantly. |
|
Colchicine |
↑ Colchicine |
0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Patients with renal or hepatic impairment should not be given colchicine with INVIRASE/ritonavir. |
|
Clarithromycin |
↑ Saquinavir ↑ Clarithromycin |
Due to the known effect of ritonavir on clarithromycin concentrations, the following dose adjustments are recommended for patients with renal impairment:
|
| Erythromycin Halofantrine Pentamidine |
Use with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE/ritonavir |
|
|
Ketoconazole itraconazole |
↔ Saquinavir ↔ Ritonavir ↑ Ketoconazole |
When INVIRASE/ritonavir and ketoconazole are coadministered, plasma concentrations of ketoconazole are increased (see |
|
Rifabutin |
↔ Saquinavir ↑ Rifabutin ↔ Ritonavir |
No dose adjustment of INVIRASE/ritonavir (1000/100 mg bid) is required if ritonavir-boosted INVIRASE is administered in combination with rifabutin. Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse events is warranted in patients receiving the combination. Consider monitoring rifabutin concentrations to ensure adequate exposure. |
|
Alprazolam, clorazepate, diazepam, flurazepam |
↑ Benzodiazepines | Clinical significance is unknown; however, a decrease in benzodiazepine dose may be needed. |
|
Intravenously administered Midazolam |
↑ Midazolam | Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, INVIRASE should not be given with orally administered midazolam |
|
Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine |
↑ Calcium channel blockers | Caution is warranted and clinical monitoring of patients is recommended. |
|
Dexamethasone |
↓ Saquinavir |
Use with caution. Saquinavir may be less effective due to decreased saquinavir plasma concentrations. |
|
|
↑ Digoxin Increases in serum digoxin concentration were greater in female subjects as compared to male subjects when digoxin was coadministered with INVIRASE/ritonavir. |
Concomitant use of INVIRASE/ritonavir with digoxin results in a significant increase in serum concentrations of digoxin. Caution should be exercised when INVIRASE/ritonavir and digoxin are coadministered; serum digoxin concentrations should be monitored and the dose of digoxin may need to be reduced when coadministered with INVIRASE/ritonavir. |
|
Bosentan |
↑ Bosentan |
In patients who have been receiving INVIRASE/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of INVIRASE/ritonavir. After at least 10 days following the initiation of INVIRASE/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. |
|
Salmeterol |
↑ Salmeterol | Concurrent administration of salmeterol with INVIRASE/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
|
Fluticasone |
↑ Fluticasone |
Concomitant use of fluticasone propionate and INVIRASE/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Coadministration of fluticasone propionate and INVIRASE/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. |
|
Atorvastatin |
↑ Atorvastatin |
Titrate atorvastatin dose carefully and use the lowest dose necessary; do not exceed atorvastatin 20 mg/day. |
|
Cyclosporine, tacrolimus, rapamycin |
↑ Immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with INVIRASE/ritonavir. |
|
Methadone |
↓ Methadone | Dosage of methadone may need to be increased when coadministered with INVIRASE/ritonavir. Use with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE/ritonavir |
|
Clozapine Haloperidol Mesoridazine Phenothiazines Thioridazine Ziprasidone |
Use with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE/ritonavir |
|
|
Ethinyl estradiol |
↓ Ethinyl estradiol | Alternative or additional contraceptive measures should be used when estrogen-based oral contraceptives and INVIRASE/ritonavir are coadministered. |
|
Sildenafil |
↑ Sildenafil ↔ Saquinavir ↑ Vardenafil ↑ Tadalafil Only the combination of sildenafil with saquinavir soft gelatin capsules has been studied at doses used for treatment of erectile dysfunction. |
May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism.
In patients receiving INVIRASE/ritonavir for at least one week, start Adcirca at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Avoid use of Adcirca during the initiation of INVIRASE/ritonavir. Stop Adcirca at least 24 hours prior to starting INVIRASE/ritonavir. After at least one week following the initiation of INVIRASE/ritonavir, resume Adcirca at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use sildenafil with caution at reduced doses of 25 mg every 48 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir. Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir. Use tadalafil with caution at reduced doses of no more than 10 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir. |
|
|
↑ Tricyclics | Therapeutic concentration monitoring is recommended for tricyclic antidepressants when coadministered with INVIRASE/ritonavir. |
|
|
↑ Saquinavir | When INVIRASE/ritonavir is co-administered with omeprazole, saquinavir concentrations are increased significantly. If omeprazole or another proton pump inhibitor is taken concomitantly with INVIRASE/ritonavir, caution is advised and monitoring for potential saquinavir toxicities is recommended, particularly gastrointestinal symptoms, increased triglycerides, deep vein thrombosis, and QT prolongation. |
|
St. John's wort |
↓ Saquinavir | Coadministration may lead to loss of virologic response and possible resistance to INVIRASE or to the class of protease inhibitors. |
| Garlic Capsules |
↓ Saquinavir | Coadministration of garlic capsules and saquinavir is not recommended due to the potential for garlic capsules to induce the metabolism of saquinavir which may result in sub-therapeutic saquinavir concentrations. |
|
|
|
| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone),gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin |
| Verapamil, diltiazem | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (> 1 quart daily) |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine | Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide | ↓ lamotrigine | Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine | Increased lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
|
a) Predictions are based on BANZEL concentrations at the maximum recommended dose of BANZEL. b) Maximum changes predicted to be in children and in patients who achieve significantly higher levels of BANZEL, as the effect of rufinamide on these AEDs is concentration-dependent. c) Larger effects in children at high doses/concentrations of AEDs. d) Phenobarbital, primidone and phenytoin were treated as a single covariate (phenobarbital-type inducers) to examine the effect of these agents on BANZEL clearance. e) All compounds of the benzodiazepine class were pooled to examine for 'class effect' on BANZEL clearance. |
||
|
|
|
|
| Carbamazepine |
|
Dependent on dose of carbamazepine |
| Lamotrigine |
|
|
| Phenobarbital |
|
Independent of dose or concentration of Phenobarbital |
| Phenytoin |
|
Independent of dose or concentration of phenytoin |
| Topiramate |
|
|
| Valproate |
|
Dependent on concentration of valproate |
| Primidone | Not Investigated |
Independent of dose or concentration of primidone |
| Benzodiazepinese) | Not Investigated |
|
| Interacting Drug | Interaction |
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
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| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
| Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) | VIAGRA 25 mg |
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| Supine | 7.4 (-0.9, 15.7) |
| Standing | 6.0 (-0.8, 12.8) |
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| Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) | VIAGRA 100 mg |
|---|---|
| Supine | 7.9 (4.6, 11.1) |
| Standing |
4.3 (-1.8,10.3) |
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| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
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Decreased Lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide |
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Addition of carbamazepine decreases Lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels. | |
| Phenobarbital/Primidone | ↓ Lamotrigine | Decreased Lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ Lamotrigine | Decreased Lamotrigine concentration approximately 40%. |
| Rifampin | ↓ Lamotrigine | Decreased Lamotrigine AUC approximately 40%. |
| Valproate |
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Increased Lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
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| Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz*, nevirapine* |
↓ lopinavir | KALETRA dose increase is recommended in all patients Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz. KALETRA should not be administered once daily in combination with efavirenz or nevirapine |
| Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine |
↑ lopinavir | Appropriate doses of the combination with respect to safety and efficacy have not been established. |
| Nucleoside Reverse Transcriptase Inhibitor: didanosine |
KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food). |
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| Nucleoside Reverse Transcriptase Inhibitor: tenofovir |
↑ tenofovir | KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir. |
| Nucleoside Reverse Transcriptase Inhibitor: abacavir zidovudine |
↓ abacavir ↓ zidovudine |
KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown. |
| HIV-1 Protease Inhibitor: amprenavir* |
↑ amprenavir ↓ lopinavir |
KALETRA should not be administered once daily in combination with amprenavir |
| HIV-1 Protease Inhibitor: fosamprenavir/ritonavir |
↓ amprenavir ↓ lopinavir |
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor: indinavir* |
↑ indinavir | Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily |
| HIV-1 Protease Inhibitor: nelfinavir* |
↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir |
KALETRA should not be administered once daily in combination with nelfinavir |
| HIV-1 Protease Inhibitor: ritonavir* |
↑ lopinavir | Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor: saquinavir* |
↑ saquinavir | The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir. |
| HIV-1 Protease Inhibitor: tipranavir |
↓ lopinavir AUC and Cmin | KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily). |
| HIV CCR5 – antagonist: maraviroc | ↑ maraviroc | Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry® (maraviroc). |
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| Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), and quinidine |
↑ antiarrhythmics | Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA. |
| Anticancer Agents: vincristine, vinblastine, dasatinib, nilotinib |
↑ anticancer agents | Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents. For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions. |
| Anticoagulant: warfarin |
Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored. | |
| Anticonvulsants: carbamazepine, phenobarbital, phenytoin |
↓ lopinavir ↓ phenytoin |
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA. |
| Antidepressant: bupropion |
↓ bupropion ↓ active metabolite, hydroxybupropion |
Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion. |
| Antidepressant: trazodone |
↑ trazodone | Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered. |
| Anti-infective: clarithromycin |
↑ clarithromycin | For patients with renal impairment, the following dosage adjustments should be considered: • For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. • For patients with CLCR < 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary. |
| Antifungals: ketoconazole*, itraconazole, voriconazole |
↑ ketoconazole ↑ itraconazole ↓ voriconazole |
High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended. Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients. |
| Anti-gout: colchicine |
↑ colchicine | Patients with renal or hepatic impairment should not be given colchicine with KALETRA. 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). |
| Antimycobacterial: rifabutin* |
↑ rifabutin and rifabutin metabolite | Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary. |
| Antimycobacterial: rifampin |
↓ lopinavir | May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone |
| Antiparasitic: atovaquone |
↓ atovaquone | Clinical significance is unknown; however, increase in atovaquone doses may be needed. |
| Benzodiazepines: parenterally administered midazolam | ↑ midazolam | Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam |
| Calcium Channel Blockers, dihydropyridine: e.g., felodipine, nifedipine, nicardipine |
↑ dihydropyridine calcium channel blockers | Caution is warranted and clinical monitoring of patients is recommended. |
| Contraceptive: ethinyl estradiol* |
↓ ethinyl estradiol | Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended. |
| Corticosteroid: dexamethasone |
↓ lopinavir | Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly. |
| disulfiram/metronidazole | KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole). | |
| Endothelin receptor antagonists: bosentan |
↑ bosentan |
In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. |
| HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin |
↑ atorvastatin ↑ rosuvastatin |
Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with KALETRA. |
| Immunosuppressants: cyclosporine, tacrolimus, rapamycin |
↑ immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA. |
| Inhaled Steroid: fluticasone |
↑ fluticasone | Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect. |
| Long-acting beta-adrenoceptor agonist: salmeterol |
↑ salmeterol | Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
| Narcotic Analgesic: methadone* fentanyl |
↓ methadone ↑ fentanyl |
Dosage of methadone may need to be increased when co-administered with KALETRA. Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA. |
| PDE5 inhibitors: sildenafil, tadalafil, vardenafil |
↑ sildenafil ↑ tadalafil ↑ vardenafil |
Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA The following dose adjustments are recommended for use of tadalafil (Adcirca®) with KALETRA: In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: It is recommended not to exceed the following doses: • Sildenafil: 25 mg every 48 hours • Tadalafil: 10 mg every 72 hours • Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events. |
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| Interacting Drug | Interaction |
|---|---|
| Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents). | Quinine sulfate capsules, USP prolongs QT interval, ECG abnormalities including QT prolongation and Torsades de Pointes. Avoid concomitant use ( |
| Other antimalarials (e.g., halofantrine, mefloquine). | ECG abnormalities including QT prolongation. Avoid concomitant use ( |
| CYP3A4 inducers or inhibitors | Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine ( |
| CYP3A4 and CYP2D6 substrates | Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug ( |
| Digoxin | Increased digoxin plasma concentration ( |
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| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine, danazol | Do not exceed 10 mg simvastatin daily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Diltiazem | Do not exceed 40 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
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| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine, danazol | Do not exceed 10 mg simvastatin daily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Diltiazem | Do not exceed 40 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
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| Amiodarone Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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| Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
| Coadministered Drug |
Dosing Schedule |
Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
Risperidone Dose Recommendation |
||
|
|
Coadministered Drug |
Risperidone |
AUC |
Cmax |
|
| Enzyme (CYP2D6) Inhibitors |
|
|
|
|
|
| Fluoxetine |
20 mg/day |
2 or 3 mg twice daily |
1.4 |
1.5 |
Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine |
10 mg/day |
4 mg/day |
1.3 |
|
Re-evaluate dosing. |
|
|
20 mg/day |
4 mg/day |
1.6 |
|
Do not exceed 8 mg/day |
|
|
40 mg/day |
4 mg/day |
1.8 |
|
|
| Enzyme (CYP3A/ PgP inducers) Inducers |
|
|
|
|
|
| Carbamazepine |
573 ± 168 mg/day |
3 mg twice daily |
0.51 |
0.55 |
Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors |
|
|
|
|
|
| Ranitidine |
150 mg twice daily |
1 mg single dose |
1.2 |
1.4 |
Dose adjustment not needed |
| Cimetidine |
400 mg twice daily |
1 mg single dose |
1.1 |
1.3 |
Dose adjustment not needed |
| Erythromycin |
500 mg four times daily |
1 mg single dose |
1.1 |
0.94 |
Dose adjustment not needed |
|
|
|
|
|
|
|
| Other Drugs |
|
|
|
|
|
| Amitriptyline |
50 mg twice daily |
3 mg twice daily |
1.2 |
1.1 |
Dose adjustment not needed |
|
|
|
|
|
||
|
|
|||
| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
|
|
|||
|
|
|||
| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone Iodide (including iodine- containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
|
|
|||
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
|
|
|||
|
|
|
||
|
|
|
||
| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
|
|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
|
|
|||
|
|
|||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
|
|
|||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
|
|
|||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
|
|
||
|
|
||
|
|
||
| Concomitant Drug |
Effect on Concentration of Lamotrigine or Concomitant Drug |
Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine ↓ levonorgestrel |
Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%. |
| Carbamazepine and carbamazepine epoxide |
↓ lamotrigine ? carbamazepine epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels. |
| Phenobarbital/Primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40%. |
| Valproate |
↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
|
|
|
|
|
|
||
|
|
||
|
|
||
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine |
Decreased lamotrigine levels approximately 50% |
|
|
↓ levonorgestrel |
Decrease in levonorgestrel component by 19% |
| Carbamazepine (CBZ) and CBZ epoxide |
↓ lamotrigine |
Addition of carbamazepine decreases lamotrigine concentration approximately 40% |
|
|
? CBZ epoxide |
May increase CBZ epoxide levels. |
| Phenobarbital/Primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40% |
| Phenytoin (PHT) |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40% |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40% |
| Valproate |
↑ lamotrigine |
Increased lamotrigine concentrations slightly more than 2-fold |
|
|
? valproate |
Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
|
|
|
| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine,danazol | Do not exceed 10 mg simvastatindaily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Diltiazem | Do not exceed 40 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
|
|
|
||
|
|
|||
| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
|
|
|||
|
|
|||
| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone Iodide (including iodine- containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
|
|
|||
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
|
|
|||
|
|
|
||
|
|
|
||
| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
|
|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
|
|
|||
|
|
|||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
|
|
|||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
|
|
|||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
|
|
|
|
|
|
||
| Dopamine / Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day). | |
|
|
||
|
|
||
| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | |
|
|
||
| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | |
|
|
||
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | |
|
|
||
|
|
|
|
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | |
|
|
||
|
|
||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | |
|
|
||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | |
|
|
||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms. | |
| % Change from Plavix (300 mg/75 mg) alone | ||||||
|---|---|---|---|---|---|---|
| Plavix plus | Cmax (ng/mL) | AUC | Platelet Inhibition |
|||
| Day 1 | Day 5 | Day 1 | Day 5 |
Day 1 | Day 5 | |
| Omeprazole |
↓46% | ↓42% | ↓45% | ↓40% | ↓39% | ↓21% |
| Pantoprazole 80 mg | ↓24% | ↓28% | ↓20% | ↓14% | ↓15% | ↓11% |
| CONCOMITANT DRUG | CLINICAL EFFECT(S) |
|---|---|
| Amphetamines, cocaine, other sympathomimetic agents | Additive hypertension, tachycardia, possibly cardiotoxicity |
| Atropine, scopolamine, antihistamines, other anticholinergic agents | Additive or super-additive tachycardia, drowsiness |
| Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants | Additive tachycardia, hypertension, drowsiness |
| Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants | Additive drowsiness and CNS depression |
| Disulfiram | A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge |
| Fluoxetine | A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days |
| Antipyrine, barbiturates | Decreased clearance of these agents, presumably via competitive inhibition of metabolism |
| Theophylline | Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco |
| Opioids | Cross-tolerance and mutual potentiation |
| Naltrexone | Oral THC effects were enhanced by opioid receptor blockade. |
| Alcohol | Increase in the positive subjective mood effects of smoked marijuana |
|
|
(Peak plasma concentration) |
(Extent of systemic exposure) |
|---|---|---|
| Erythromycin (500 mg every 8 hrs) |
+82% | +109% |
| Ketoconazole (400 mg once daily) |
+135% | +164% |
|
|
|
|
|
|
| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
|
|
|
|
|
|
| Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
|
|
|
| Amiodarone Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
|
|
|
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
|
|
|
|
|
|
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
| Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
|
|
|
|
|
|
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
|
|
|
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
|
|
|
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine | Do not exceed 10 mg atorvastatin daily |
| Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir) | Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used. |
|
|
|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
| Co-administered Drug | Dosing Schedule | Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (Ratio |
Risperidone Dose Recommendation | ||
| Co-administered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6) Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
|
Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide |
|
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels. | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate |
|
Increased lamotrigine concentrations slightly more than 2 fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
|
|
|
|
|
|
||
| Dopamine / Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day). | |
|
|
||
|
|
||
| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | |
|
|
||
| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | |
|
|
||
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | |
|
|
||
|
|
|
|
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | |
|
|
||
|
|
||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | |
|
|
||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | |
|
|
||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms. | |
|
|
|||
| DRUG | DESCRIPTION OF INTERACTION | ||
| Sulfonylureas | Hypoglycemia potentiated. | ||
| Methotrexate | Decreases tubular reabsorption; clinical toxicity from methotrexate can result. | ||
| Oral Anticoagulants | Increased bleeding. | ||
|
|
|||
| DRUG | DESCRIPTION OF INTERACTION | ||
| Corticosteroids | Decreases plasma salicylate level; tapering doses of steroids may promote salicylism. | ||
| Acidifying Agents | Increases plasma salicylate levels. | ||
| Alkanizing Agents | Decreased plasma salicylate levels. | ||
|
|
|||
| DRUG | DESCRIPTION OF INTERACTION | ||
| Heparin | Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients. | ||
| Pyrazinamide | Inhibits pyrazinamide-induced hyperuricemia. | ||
| Uricosuric Agents | Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited. | ||
| The following alterations of laboratory tests have been reported during salicylate therapy: | |||
| LABORATORY TESTS | EFFECT OF SALICYLATES | ||
| Thyroid Function | Decreased PBI; increased t3 uptake. | ||
| Urinary Sugar | False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.). | ||
| 5-Hydroxyindole acetic acid | False negative with fluorometric test. | ||
| Acetone ketone bodies | False positive FeCI3 in Gerhardt reaction; red color persists with boiling. | ||
| 17-OH corticosteroids | False reduced values with >4.8g q.d. salicylate. | ||
| Vanilmandelic acid | False reduced values. | ||
| Uric Acid | May increase or decrease depending on dose. | ||
| Prothrombin | Decreased levels; slightly increased prothrombin time. | ||
| Concomitant Drug Class: Drug Name |
Effect on Concentration of Darunavir or Concomitant Drug | Clinical Comment |
|---|---|---|
|
|
||
| didanosine | ↔ darunavir ↔ didanosine |
Didanosine should be administered one hour before or two hours after PREZISTA/ritonavir (which are administered with food). |
|
|
||
| indinavir (The reference regimen for indinavir was indinavir/ritonavir 800/100 mg twice daily.) |
↑ darunavir ↑ indinavir |
The appropriate dose of indinavir in combination with PREZISTA/ritonavir has not been established. |
| lopinavir/ritonavir | ↓ darunavir ↔ lopinavir |
Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer lopinavir/ritonavir and PREZISTA, with or without ritonavir. |
| saquinavir | ↓ darunavir ↔ saquinavir |
Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer saquinavir and PREZISTA, with or without ritonavir. |
|
|
||
| maraviroc | ↑ maraviroc | Maraviroc concentrations are increased when co-administered with PREZISTA/ritonavir. When used in combination with PREZISTA/ritonavir, the dose of maraviroc should be 150 mg twice daily. |
|
|
||
|
bepridil, lidocaine (systemic), quinidine, amiodarone, flecainide, propafenone |
↑ antiarrhythmics | Concentrations of these drugs may be increased when co-administered with PREZISTA/ritonavir. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when co-administered with PREZISTA/ritonavir. |
| digoxin | ↑ digoxin | The lowest dose of digoxin should initially be prescribed. The serum digoxin concentrations should be monitored and used for titration of digoxin dose to obtain the desired clinical effect. |
|
warfarin |
↓ warfarin ↔ darunavir |
Warfarin concentrations are decreased when co-administered with PREZISTA/ritonavir. It is recommended that the international normalized ratio (INR) be monitored when warfarin is combined with PREZISTA/ritonavir. |
|
carbamazepine |
↔ darunavir ↑ carbamazepine |
The dose of either darunavir/ritonavir or carbamazepine does not need to be adjusted when initiating co-administration with darunavir/ritonavir and carbamazepine. Clinical monitoring of carbamazepine concentrations and its dose titration is recommended to achieve the desired clinical response. |
|
phenobarbital, phenytoin |
↔ darunavir ↓ phenytoin ↓ phenobarbital |
Co-administration of PREZISTA/ritonavir may cause a decrease in the steady-state concentrations of phenytoin and phenobarbital. Phenytoin and phenobarbital levels should be monitored when co-administering with PREZISTA/ritonavir. |
|
trazodone, desipramine |
↑ trazodone ↑ desipramine |
Concomitant use of trazodone or desipramine and PREZISTA/ritonavir may increase plasma concentrations of trazodone or desipramine which may lead to adverse events such as nausea, dizziness, hypotension and syncope. If trazodone or desipramine is used with PREZISTA/ritonavir, the combination should be used with caution, and a lower dose of trazodone or desipramine should be considered. |
|
clarithromycin |
↔ darunavir ↑ clarithromycin |
No dose adjustment of the combination is required for patients with normal renal function. For patients with renal impairment, the following dose adjustments should be considered:
|
|
ketoconazole, itraconazole, voriconazole |
↑ ketoconazole ↑ darunavir ↑ itraconazole (not studied) ↓ voriconazole (not studied) |
Ketoconazole and itraconazole are potent inhibitors as well as substrates of CYP3A. Concomitant systemic use of ketoconazole, itraconazole, and darunavir/ritonavir may increase plasma concentration of darunavir. |
| Plasma concentrations of ketoconazole or itraconazole may be increased in the presence of darunavir/ritonavir. When co-administration is required, the daily dose of ketoconazole or itraconazole should not exceed 200 mg. | ||
| Plasma concentrations of voriconazole may be decreased in the presence of darunavir/ritonavir. Voriconazole should not be administered to patients receiving darunavir/ritonavir unless an assessment of the benefit/risk ratio justifies the use of voriconazole. | ||
|
colchicine |
↑ colchicine |
0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days. If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Patients with renal or hepatic impairment should not be given colchicine with PREZISTA/ritonavir. |
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rifabutin |
↑ darunavir ↑ rifabutin ↑ 25- |
Dose reduction of rifabutin by at least 75% of the usual dose (300 mg once daily) is recommended (i.e., a maximum dose of 150 mg every other day). Increased monitoring for adverse events is warranted in patients receiving this combination and further dose reduction of rifabutin may be necessary. |
| The reference regimen for rifabutin was 300 mg once daily | ||
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metoprolol, timolol |
↑ beta-blockers | Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir. |
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parenterally administered midazolam |
↑ midazolam | Concomitant use of parenteral midazolam with PREZISTA/ritonavir may increase plasma concentrations of midazolam. Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Co-administration of oral midazolam with PREZISTA/ritonavir is CONTRAINDICATED. |
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felodipine, nifedipine, nicardipine |
↑ calcium channel blockers | Plasma concentrations of calcium channel blockers (e.g., felodipine, nifedipine, nicardipine) may increase when PREZISTA/ritonavir are co-administered. Caution is warranted and clinical monitoring of patients is recommended. |
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dexamethasone |
↓ darunavir | Systemic dexamethasone induces CYP3A and can thereby decrease darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA. |
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fluticasone |
↑ fluticasone | Concomitant use of inhaled fluticasone and PREZISTA/ritonavir may increase plasma concentrations of fluticasone. Alternatives should be considered, particularly for long-term use. |
|
bosentan |
↑ bosentan |
In patients who have been receiving PREZISTA/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of PREZISTA/ritonavir. After at least 10 days following the initiation of PREZISTA/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. |
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NS3-4A protease inhibitors: boceprevir telaprevir |
↓ darunavir ↓ boceprevir ↓ telaprevir |
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pravastatin, atorvastatin, rosuvastatin |
↑ pravastatin ↑ atorvastatin ↑ rosuvastatin |
Titrate atorvastatin, pravastatin or rosuvastatin dose carefully and use the lowest necessary dose while monitoring for safety. Do not exceed atorvastatin 20 mg/day. |
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cyclosporine, tacrolimus, sirolimus |
↑ immunosuppressants | Plasma concentrations of cyclosporine, tacrolimus or sirolimus may be increased when co-administered with PREZISTA/ritonavir. Therapeutic concentration monitoring of the immunosuppressive agent is recommended when co-administered with PREZISTA/ritonavir. |
|
salmeterol |
↑ salmeterol | Concurrent administration of salmeterol and PREZISTA/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
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methadone, buprenorphine, buprenorphine/naloxone |
↓ methadone ↔ buprenorphine, naloxone ↑ norbuprenorphine (metabolite) |
No adjustment of methadone dosage is required when initiating co-administration of PREZISTA/ritonavir. However, clinical monitoring is recommended as the dose of methadone during maintenance therapy may need to be adjusted in some patients. No dose adjustment for buprenorphine or buprenorphine/naloxone is required with concurrent administration of PREZISTA/ritonavir. Clinical monitoring is recommended if PREZISTA/ritonavir and buprenorphine or buprenorphine/naloxone are coadministered. |
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risperidone, thioridazine |
↑ neuroleptics | A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir. |
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ethinyl estradiol, norethindrone |
↓ ethinyl estradiol ↓ norethindrone |
Plasma concentrations of ethinyl estradiol are decreased due to induction of its metabolism by ritonavir. Alternative methods of nonhormonal contraception are recommended. |
|
sildenafil, vardenafil, tadalafil |
↑ PDE-5 inhibitors (only the use of sildenafil at doses used for treatment of erectile dysfunction has been studied with PREZISTA/ritonavir) |
Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg dose in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours can be used with increased monitoring for PDE-5 inhibitor-associated adverse events. |
|
sertraline, paroxetine |
↔ darunavir ↓ sertraline ↓ paroxetine |
If sertraline or paroxetine is co-administered with PREZISTA/ritonavir, the recommended approach is a careful dose titration of the SSRI based on a clinical assessment of antidepressant response. In addition, patients on a stable dose of sertraline or paroxetine who start treatment with PREZISTA/ritonavir should be monitored for antidepressant response. |
| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
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| HIV-1 Protease Inhibitor: atazanavir |
When co-administered with reduced doses of atazanavir and ritonavir ↑ atazanavir (↑ AUC, ↑ Cmax, ↑ Cmin) |
Atazanavir plasma concentrations achieved with atazanavir 300 mg once daily and ritonavir 100 mg once daily are higher than those achieved with atazanavir 400 mg once daily. See the complete prescribing information for Reyataz® (atazanavir) for details on co-administration of atazanavir 300 mg once daily with ritonavir 100 mg once daily. |
| HIV-1 Protease Inhibitor: darunavir |
When co-administered with reduced doses of ritonavir ↑ darunavir (↑ AUC, ↑ Cmax, ↑ Cmin) |
See the complete prescribing information for Prezista® (darunavir) for details on co-administration of darunavir 600 mg twice daily with ritonavir 100 mg twice daily or darunavir 800 mg once daily with ritonavir 100 mg once daily. |
| HIV-1 Protease Inhibitor: fosamprenavir |
When co-administered with reduced doses of ritonavir ↑ amprenavir (↑ AUC, ↑ Cmax, ↑ Cmin) |
See the complete prescribing information for Lexiva® (fosamprenavir) for details on co-administration of fosamprenavir 700 mg twice daily with ritonavir 100 mg twice daily, fosamprenavir 1400 mg once daily with ritonavir 200 mg once daily or fosamprenavir 1400 mg once daily with ritonavir 100 mg once daily. |
| HIV-1 Protease Inhibitor: indinavir |
When co-administered with reduced doses of indinavir and ritonavir ↑ indinavir (↔ AUC, ↓ Cmax, ↑ Cmin) |
Alterations in concentrations are noted when reduced doses of indinavir are co-administered with NORVIR. Appropriate doses for this combination, with respect to efficacy and safety, have not been established. |
| HIV-1 Protease Inhibitor: saquinavir |
When co-administered with reduced doses of ritonavir ↑ saquinavir (↑ AUC, ↑ Cmax, ↑ Cmin) |
See the complete prescribing information for Invirase® (saquinavir) for details on co-administration of saquinavir 1000 mg twice daily with ritonavir 100 mg twice daily. Saquinavir/ritonavir should not be given together with rifampin, due to the risk of severe hepatotoxicity (presenting as increased hepatic transaminases) if the three drugs are given together. |
| HIV-1 Protease Inhibitor: tipranavir |
When co-administered with reduced doses of ritonavir ↑ tipranavir (↑ AUC, ↑ Cmax, ↑ Cmin) |
See the complete prescribing information for Aptivus® (tipranavir) for details on co-administration of tipranavir 500 mg twice daily with ritonavir 200 mg twice daily. There have been reports of clinical hepatitis and hepatic decompensation including some fatalities. All patients should be followed closely with clinical and laboratory monitoring, especially those with chronic hepatitis B or C co-infection, as these patients have an increased risk of hepatotoxicity. Liver function tests should be performed prior to initiating therapy with tipranavir/ritonavir, and frequently throughout the duration of treatment. |
| Non-Nucleoside Reverse Transcriptase Inhibitor: delavirdine |
↑ ritonavir (↑AUC, ↑Cmax, ↑ Cmin) | Appropriate doses of this combination with respect to safety and efficacy have not been established. |
| HIV-1 CCR5 – antagonist: maraviroc |
↑ maraviroc | Concurrent administration of maraviroc with ritonavir will increase plasma levels of maraviroc. For specific dosage adjustment recommendations, please refer to the complete prescribing information for Selzentry® (maraviroc). |
| Integrase Inhibitor: Raltegravir |
↓ raltegravir | The effects of ritonavir on raltegravir with ritonavir dosage regimens greater than 100 mg twice daily have not been evaluated, however raltegravir concentrations may be decreased with ritonavir coadministration. |
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| Analgesics, Narcotic: tramadol, propoxyphene |
A dose decrease may be needed for these drugs when co-administered with ritonavir. | |
| Anesthetic: meperidine |
↓ meperidine/ ↑ normeperidine (metabolite) | Dosage increase and long-term use of meperidine with ritonavir are not recommended due to the increased concentrations of the metabolite normeperidine which has both analgesic activity and CNS stimulant activity (e.g., seizures). |
| Antialcoholics: disulfiram/metronidazole |
Ritonavir formulations contain alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole). | |
| Antiarrhythmics: disopyramide, lidocaine, mexiletine |
↑antiarrhythmics | Caution is warranted and therapeutic concentration monitoring is recommended for antiarrhythmics when co-administered with ritonavir, if available. |
| Anticancer Agents: dasatinib, nilotinib, vincristine, vinblastine |
↑ anticancer agents | Concentrations of these drugs may be increased when co-administered with ritonavir resulting in the potential for increased adverse events usually associated with these anticancer agents. For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when ritonavir is administered concurrently with vincristine or vinblastine. Clinicians should be aware that if the ritonavir containing regimen is withheld for a prolonged period, consideration should be given to altering the regimen to not include a CYP3A or P-gp inhibitor in order to control HIV-1 viral load. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as NORVIR. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions. |
| Anticoagulant: warfarin |
↓ R-warfarin ↓↑ S-warfarin |
Initial frequent monitoring of the INR during ritonavir and warfarin co-administration is indicated. |
| Anticoagulant: rivaroxaban |
↑ rivaroxaban | Avoid concomitant use of rivaroxaban and ritonavir. Co-administration of ritonavir and rivaroxaban is expected to result in increased exposure of rivaroxaban which may lead to risk of increased bleeding. |
| Anticonvulsants: carbamazepine, clonazepam, ethosuximide |
↑anticonvulsants | Use with caution. A dose decrease may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available. |
| Anticonvulsants: divalproex, lamotrigine, phenytoin |
↓anticonvulsants | Use with caution. A dose increase may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available. |
| Antidepressants: nefazodone, selective serotonin reuptake inhibitors (SSRIs): e.g. fluoxetine, paroxetine, tricyclics: e.g. amitriptyline, nortriptyline |
↑antidepressants | A dose decrease may be needed for these drugs when co-administered with ritonavir. |
| Antidepressant: bupropion |
↓ bupropion ↓ active metabolite, hydroxybupropion |
Concurrent administration of bupropion with ritonavir may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving ritonavir and bupropion concurrently should be monitored for an adequate clinical response to bupropion. |
| Antidepressant: desipramine |
↑ desipramine | Dosage reduction and concentration monitoring of desipramine is recommended. |
| Antidepressant: trazodone |
↑ trazodone | Concomitant use of trazodone and NORVIR increases plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and NORVIR. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered. |
| Antiemetic: dronabinol |
↑ dronabinol | A dose decrease of dronabinol may be needed when co-administered with ritonavir. |
| Antifungal: ketoconazole itraconazole voriconazole |
↑ ketoconazole ↑ itraconazole ↓ voriconazole |
High doses of ketoconazole or itraconazole (greater than 200 mg per day) are not recommended. Co-administration of voriconazole and ritonavir doses of 400 mg every 12 hours or greater is contraindicated. Co-administration of voriconazole and ritonavir 100 mg should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. |
| Anti-gout: colchicine |
↑ colchicine | Patients with renal or hepatic impairment should not be given colchicine with ritonavir. 0.6 mg (one tablet) for one dose, followed by 0.3 mg (half tablet) one hour later. Dose to be repeated no earlier than three days. If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). |
| Anti-infective: clarithromycin |
↑ clarithromycin | For patients with renal impairment the following dosage adjustments should be considered: • For patients with CLCR 30 to 60 mL per min the dose of clarithromycin should be reduced by 50%. • For patients with CLCR less than 30 mL per min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary. |
| Antimycobacterial: rifabutin |
↑ rifabutin and rifabutin metabolite | Dosage reduction of rifabutin by at least three-quarters of the usual dose of 300 mg per day is recommended (e.g., 150 mg every other day or three times a week). Further dosage reduction may be necessary. |
| Antimycobacterial: rifampin |
↓ ritonavir | May lead to loss of virologic response. Alternate antimycobacterial agents such as rifabutin should be considered (see Antimycobacterial: rifabutin, for dose reduction recommendations). |
| Antiparasitic: atovaquone |
↓ atovaquone | Clinical significance is unknown; however, increase in atovaquone dose may be needed. |
| Antiparasitic: quinine |
↑ quinine | A dose decrease of quinine may be needed when co-administered with ritonavir. |
| β-Blockers: metoprolol, timolol |
↑ Beta-Blockers | Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with ritonavir. |
| Bronchodilator: theophylline |
↓ theophylline | Increased dosage of theophylline may be required; therapeutic monitoring should be considered. |
| Calcium channel blockers: diltiazem, nifedipine, verapamil |
↑ calcium channel blockers | Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with ritonavir. |
| Digoxin | ↑ digoxin | Concomitant administration of ritonavir with digoxin may increase digoxin levels. Caution should be exercised when co-administering ritonavir with digoxin, with appropriate monitoring of serum digoxin levels. |
| Endothelin receptor antagonists: bosentan |
↑ bosentan |
In patients who have been receiving ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability Discontinue use of bosentan at least 36 hours prior to initiation of ritonavir. After at least 10 days following the initiation of ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. |
| HMG-CoA Reductase Inhibitor: atorvastatin rosuvastatin |
↑ atorvastatin ↑ rosuvastatin |
Titrate atorvastatin and rosuvastatin dose carefully and use the lowest necessary dose. If NORVIR is used with another protease inhibitor, see the complete prescribing information for the concomitant protease inhibitor for details on co-administration with atorvastatin and rosuvastatin. |
| Immunosuppressants: cyclosporine, tacrolimus, sirolimus (rapamycin) |
↑ immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with ritonavir. |
| Inhaled or Intranasal Steroid: e.g. fluticasone budesonide |
↑ glucocorticoids | Concomitant use of ritonavir and fluticasone or other glucocorticoids that are metabolized by CYP3A is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. Concomitant use may result in increased steroid concentrations and reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during postmarketing use in patients when ritonavir has been coadministered with fluticasone propionate or budesonide. |
| Long-acting beta-adrenoceptor agonist: salmeterol |
↑ salmeterol | Concurrent administration of salmeterol and ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
| Narcotic Analgesic: methadone fentanyl |
↓ methadone ↑ fentanyl |
Dosage increase of methadone may be considered. Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with NORVIR. |
| Neuroleptics: perphenazine, risperidone, thioridazine |
↑ neuroleptics | A dose decrease may be needed for these drugs when co-administered with ritonavir. |
| Oral Contraceptives or Patch Contraceptives: ethinyl estradiol |
↓ ethinyl estradiol | Alternate methods of contraception should be considered. |
| PDE5 Inhibitors: avanafil sildenafil, tadalafil, vardenafil |
↑ avanafil ↑ sildenafil ↑ tadalafil ↑ vardenafil |
Do not use ritonavir with avanafil because a safe and effective avanafil dosage regimen has not been established. Particular caution should be used when prescribing sildenafil, tadalafil or vardenafil in patients receiving ritonavir. Coadministration of ritonavir with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse events, including hypotension, syncope, visual changes, and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with ritonavir [see The following dose adjustments are recommended for use of tadalafil (AdcircaTM) with ritonavir: In patients receiving ritonavir for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Avoid use of ADCIRCA during the initiation of ritonavir. Stop ADCIRCA at least 24 hours prior to starting ritonavir. After at least one week following the initiation of ritonavir, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for the treatment of erectile dysfunction: It is recommended not to exceed the following doses: • Sildenafil: 25 mg every 48 hours • Tadalafil: 10 mg every 72 hours • Vardenafil: 2.5 mg every 72 hours. Use with increased monitoring for adverse events. |
| Sedative/hypnotics: buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem |
↑ sedative/hypnotics | A dose decrease may be needed for these drugs when co-administered with ritonavir. |
| Sedative/hypnotics: Parenteral midazolam |
↑ midazolam | Co-administration of oral midazolam with NORVIR is CONTRAINDICATED. Concomitant use of parenteral midazolam with NORVIR may increase plasma concentrations of midazolam. Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. |
| Steroids (systemic): e.g. budesonide dexamethasone, prednisone |
↑ glucocorticoids | Concomitant use of glucocorticoids that are metabolized by CYP3A is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. Concomitant use may result in increased steroid concentrations and reduced serum cortisol concentrations. This may increase the risk for development of systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression. |
| Stimulant: methamphetamine |
↑ methamphetamine | Use with caution. A dose decrease of methamphetamine may be needed when co-administered with ritonavir. |
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| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine,danazol | Do not exceed 10 mg simvastatindaily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Diltiazem | Do not exceed 40 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
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| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
| Coadministered Drug |
Dosing Schedule |
Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio |
Risperidone Dose Recommendation |
||
| |
Coadministered Drug |
Risperidone |
AUC |
Cmax
|
|
| Enzyme (CYP2D6) Inhibitors |
|||||
| Fluoxetine |
20 mg/day |
2 or 3 mg twice daily |
1.4 |
1.5 |
Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine |
10 mg/day |
4 mg/day |
1.3 |
- |
Re-evaluate dosing. Do not exceed 8 mg/day |
| |
20 mg/day |
4 mg/day |
1.6 |
- |
|
| |
40 mg/day |
4 mg/day |
1.8 |
- |
|
| Enzyme (CYP3A/ PgP inducers) Inducers |
|||||
| Carbamazepine |
573 ± 168 mg/day |
3 mg twice daily |
0.51 |
0.55 |
Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors |
|||||
| Ranitidine |
150 mg twice daily |
1 mg single dose |
1.2 |
1.4 |
Dose adjustment not needed |
| Cimetidine |
400 mg twice daily |
1 mg single dose |
1.1 |
1.3 |
Dose adjustment not needed |
| Erythromycin |
500 mg four times daily |
1 mg single dose |
1.1 |
0.94 |
Dose adjustment not needed |
| Other Drugs |
|||||
| Amitriptyline |
50 mg twice daily |
3 mg twice daily |
1.2 |
1.1 |
Dose adjustment not needed |
|
|
(Peak plasma concentration) |
(Extent of systemic exposure) |
|---|---|---|
| Erythromycin (500 mg every 8 hrs) |
+82% | +109% |
| Ketoconazole (400 mg once daily) |
+135% | +164% |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
|
Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide |
|
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels. | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate |
|
Increased lamotrigine concentrations slightly more than 2 fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
|
Specific Drugs |
|
|
|---|---|---|
|
a For magnitude of interactions see |
||
|
b See |
||
| c In combination with atazanavir 300 mg and ritonavir 100 mg once daily. | ||
| d In combination with atazanavir 400 mg once daily. | ||
|
|
||
|
didanosine buffered formulations enteric-coated (EC) capsules |
↓ atazanavir ↓ didanosine |
Coadministration of REYATAZ with didanosine buffered tablets resulted in a marked decrease in atazanavir exposure. It is recommended that REYATAZ be given (with food) 2 h before or 1 h after didanosine buffered formulations. Simultaneous administration of didanosine EC and REYATAZ with food results in a decrease in didanosine exposure. Thus, REYATAZ and didanosine EC should be administered at different times. |
|
|
↓ atazanavir ↑ tenofovir |
Tenofovir may decrease the AUC and Cmin of atazanavir. When coadministered with tenofovir, it is recommended that REYATAZ 300 mg be given with ritonavir 100 mg and tenofovir 300 mg (all as a single daily dose with food). |
|
|
↓ atazanavir | Efavirenz decreases atazanavir exposure. If REYATAZ is combined with efavirenz, REYATAZ 400 mg (two 200-mg capsules) with ritonavir 100 mg should be administered once daily all as a single dose with food, and efavirenz 600 mg should be administered once daily on an empty stomach, preferably at bedtime. Do not coadminister REYATAZ with efavirenz in treatment-experienced patients due to decreased atazanavir exposure. |
| nevirapine | ↓ atazanavir ↑ nevirapine |
Do not coadminister REYATAZ with nevirapine because:
|
|
saquinavir (soft gelatin capsules) |
↑ saquinavir | Appropriate dosing recommendations for this combination, with or without ritonavir, with respect to efficacy and safety have not been established. In a clinical study, saquinavir 1200 mg coadministered with REYATAZ 400 mg and tenofovir 300 mg (all given once daily) plus nucleoside analogue reverse transcriptase inhibitors did not provide adequate efficacy [see |
| ritonavir | ↑ atazanavir | If REYATAZ is coadministered with ritonavir, it is recommended that REYATAZ 300 mg once daily be given with ritonavir 100 mg once daily with food. See the complete prescribing information for NORVIR® (ritonavir) for information on drug interactions with ritonavir. |
| others | ↑ other protease inhibitor |
|
|
|
||
|
boceprevir |
↓ atazanavir ↓ ritonavir |
Concomitant administration of boceprevir and atazanavir/ritonavir resulted in reduced steady-state exposures to atazanavir and ritonavir. Coadministration of REYATAZ/ritonavir and boceprevir is not recommended. |
| telaprevir | ↓ telaprevir ↑ atazanavir |
Concomitant administration of telaprevir and atazanavir/ritonavir resulted in reduced steady-state telaprevir exposure, while steady-state atazanavir exposure was increased. |
|
|
||
|
|
↓ atazanavir | Reduced plasma concentrations of atazanavir are expected if antacids, including buffered medications, are administered with REYATAZ. REYATAZ should be administered 2 hours before or 1 hour after these medications. |
|
|
↑ amiodarone, bepridil, lidocaine (systemic), quinidine | Coadministration with REYATAZ has the potential to produce serious and/or life-threatening adverse events and has not been studied. Caution is warranted and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ (atazanavir sulfate). |
|
|
↑ warfarin | Coadministration with REYATAZ has the potential to produce serious and/or life-threatening bleeding and has not been studied. It is recommended that INR (International Normalized Ratio) be monitored. |
|
|
↑ tricyclic antidepressants | Coadministration with REYATAZ has the potential to produce serious and/or life-threatening adverse events and has not been studied. Concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ. |
| trazodone | ↑ trazodone | Concomitant use of trazodone and REYATAZ with or without ritonavir may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as REYATAZ, the combination should be used with caution and a lower dose of trazodone should be considered. |
|
carbamazepine |
↓ atazanavir ↑ carbamazepine |
Plasma concentrations of atazanavir may be decreased when carbamazepine is administered with REYATAZ without ritonavir. Coadministration of carbamazepine and REYATAZ without ritonavir is not recommended. Ritonavir may increase plasma levels of carbamazepine. If patients beginning treatment with REYATAZ/ritonavir have been titrated to a stable dose of carbamazepine, a dose reduction for carbamazepine may be necessary. |
| phenytoin, phenobarbital | ↓ atazanavir ↓ phenytoin ↓ phenobarbital |
Plasma concentrations of atazanavir may be decreased when phenytoin or phenobarbital is administered with REYATAZ without ritonavir. Coadministration of phenytoin or phenobarbital and REYATAZ without ritonavir is not recommended. Ritonavir may decrease plasma levels of phenytoin and phenobarbital. When REYATAZ with ritonavir is coadministered with either phenytoin or phenobarbital, a dose adjustment of phenytoin or phenobarbital may be required. |
| lamotrigine | ↓ lamotrigine | Coadministration of lamotrigine and REYATAZ |
|
ketoconazole, itraconazole |
↑ ketoconazole ↑ itraconazole |
Coadministration of ketoconazole has only been studied with REYATAZ without ritonavir (negligible increase in atazanavir AUC and Cmax). Due to the effect of ritonavir on ketoconazole, high doses of ketoconazole and itraconazole (>200 mg/day) should be used cautiously with REYATAZ/ritonavir. |
| voriconazole |
↓ voriconazole ↓ atazanavir ↑ voriconazole ↓ atazanavir |
Voriconazole should not be administered to patients receiving REYATAZ/ritonavir, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Patients should be carefully monitored for voriconazole-associated adverse events and loss of either voriconazole or atazanavir efficacy during the coadministration of voriconazole and REYATAZ/ritonavir. Coadministration of voriconazole with REYATAZ (without ritonavir) may affect atazanavir concentrations; however, no data are available. |
|
|
↑ colchicine | REYATAZ should not be coadministered with colchicine to patients with renal or hepatic impairment. Treatment of gout flares:
|
|
|
↑ rifabutin | A rifabutin dose reduction of up to 75% (eg, 150 mg every other day or 3 times per week) is recommended. Increased monitoring for rifabutin-associated adverse reactions including neutropenia is warranted. |
|
|
↑ midazolam | Concomitant use of parenteral midazolam with REYATAZ may increase plasma concentrations of midazolam. Coadministration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Coadministration of oral midazolam with REYATAZ is CONTRAINDICATED. |
|
|
↑ diltiazem and desacetyl-diltiazem | Caution is warranted. A dose reduction of diltiazem by 50% should be considered. ECG monitoring is recommended. Coadministration of REYATAZ/ritonavir with diltiazem has not been studied. |
| felodipine, nifedipine, nicardipine, and verapamil | ↑ calcium channel blocker | Caution is warranted. Dose titration of the calcium channel blocker should be considered. ECG monitoring is recommended. |
|
|
↓ atazanavir ↑ bosentan |
Plasma concentrations of atazanavir may be decreased when bosentan is administered with REYATAZ without ritonavir. Coadministration of bosentan and REYATAZ without ritonavir is not recommended.
|
|
|
↑ atorvastatin ↑ rosuvastatin |
Titrate atorvastatin dose carefully and use the lowest necessary dose. Rosuvastatin dose should not exceed 10 mg/day. The risk of myopathy, including rhabdomyolysis, may be increased when HIV protease inhibitors, including REYATAZ, are used in combination with these drugs. |
|
|
↓ atazanavir | Plasma concentrations of atazanavir were substantially decreased when REYATAZ 400 mg once daily was administered simultaneously with famotidine 40 mg twice daily, which may result in loss of therapeutic effect and development of resistance. |
|
REYATAZ 300 mg with ritonavir 100 mg once daily with food should be administered simultaneously with, and/or at least 10 hours after, a dose of the H2-receptor antagonist. An H2-receptor antagonist dose comparable to famotidine 20 mg once daily up to a dose comparable to famotidine 40 mg twice daily can be used with REYATAZ 300 mg with ritonavir 100 mg in treatment-naive patients. OR For patients unable to tolerate ritonavir, REYATAZ 400 mg once daily with food should be administered at least 2 hours before and at least 10 hours after a dose of the H2-receptor antagonist. No single dose of the H2-receptor antagonist should exceed a dose comparable to famotidine 20 mg, and the total daily dose should not exceed a dose comparable to famotidine 40 mg. However, REYATAZ should not be used without ritonavir in pregnant women. |
||
|
Whenever an H2-receptor antagonist is given to a patient receiving REYATAZ with ritonavir, the H2-receptor antagonist dose should not exceed a dose comparable to famotidine 20 mg twice daily, and the REYATAZ and ritonavir doses should be administered simultaneously with, and/or at least 10 hours after, the dose of the H2-receptor antagonist.
|
||
|
|
↓ ethinyl estradiol ↑ norgestimatec |
Use with caution if coadministration of REYATAZ or REYATAZ/ritonavir with oral contraceptives is considered. If an oral contraceptive is administered with REYATAZ plus ritonavir, it is recommended that the oral contraceptive contain at least 35 mcg of ethinyl estradiol. If REYATAZ is administered without ritonavir, the oral contraceptive should contain no more than 30 mcg of ethinyl estradiol. |
| ↑ ethinyl estradiol ↑ norethindroned |
Potential safety risks include substantial increases in progesterone exposure. The long-term effects of increases in concentration of the progestational agent are unknown and could increase the risk of insulin resistance, dyslipidemia, and acne. Coadministration of REYATAZ or REYATAZ/ritonavir with other hormonal contraceptives (eg, contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than norethindrone or norgestimate, or less than 25 mcg of ethinyl estradiol, has not been studied; therefore, alternative methods of contraception are recommended. |
|
|
|
↑ immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with REYATAZ (atazanavir sulfate). |
|
|
↑ salmeterol | Coadministration of salmeterol with REYATAZ is not recommended. Concomitant use of salmeterol and REYATAZ may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia. |
|
|
|
Concomitant use of fluticasone propionate and REYATAZ (without ritonavir) may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use. |
|
|
Concomitant use of fluticasone propionate and REYATAZ/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression, have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Coadministration of fluticasone propionate and REYATAZ/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects [see |
|
|
|
↑ clarithromycin ↓ 14-OH clarithromycin ↑ atazanavir |
Increased concentrations of clarithromycin may cause QTc prolongations; therefore, a dose reduction of clarithromycin by 50% should be considered when it is coadministered with REYATAZ. In addition, concentrations of the active metabolite 14-OH clarithromycin are significantly reduced; consider alternative therapy for indications other than infections due to |
|
|
↑ buprenorphine ↑ norbuprenorphine |
Coadministration of buprenorphine and REYATAZ with or without ritonavir increases the plasma concentration of buprenorphine and norbuprenorphine. Coadministration of REYATAZ plus ritonavir with buprenorphine warrants clinical monitoring for sedation and cognitive effects. A dose reduction of buprenorphine may be considered. Coadministration of buprenorphine and REYATAZ with ritonavir is not expected to decrease atazanavir plasma concentrations. Coadministration of buprenorphine and REYATAZ without ritonavir may decrease atazanavir plasma concentrations. REYATAZ without ritonavir should not be coadministered with buprenorphine. |
|
|
↑ sildenafil ↑ tadalafil ↑ vardenafil |
Coadministration with REYATAZ has not been studied but may result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism.
|
|
|
|
|
|
|
↓ atazanavir | Plasma concentrations of atazanavir were substantially decreased when REYATAZ 400 mg or REYATAZ 300 mg/ritonavir 100 mg once daily was administered with omeprazole 40 mg once daily, which may result in loss of therapeutic effect and development of resistance. |
|
The proton-pump inhibitor dose should not exceed a dose comparable to omeprazole 20 mg and must be taken approximately 12 hours prior to the REYATAZ 300 mg with ritonavir 100 mg dose. |
||
|
Proton-pump inhibitors should not be used in treatment-experienced patients receiving REYATAZ. |
||
|
|
|
|
|
Avoid atorvastatin
|
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
|
|
Do not exceed 20 mg atorvastatin daily
|
| HIV protease inhibitor (nelfinavir) | Do not exceed 40 mg atorvastatin daily |
| Coadministered drug (Postulated effect on CYP450/UGT) |
Dose schedules | Effect on asenapine pharmacokinetics | Recommendation | ||
|---|---|---|---|---|---|
| Coadministered drug | Asenapine | Cmax | AUC0-∞ | ||
| Fluvoxamine (CYP1A2 inhibitor) |
25 mg twice daily for 8 days | 5-mg Single Dose | +13% | +29% | Coadminister with caution |
| Paroxetine (CYP2D6 inhibitor) |
20 mg once daily for 9 days | 5-mg Single Dose | –13% | –9% | No SAPHRIS dose adjustment required |
| Imipramine (CYP1A2/2C19/3A4 inhibitor) |
75-mg Single Dose | 5-mg Single Dose | +17% | +10% | No SAPHRIS dose adjustment required |
| Cimetidine (CYP3A4/2D6/1A2 inhibitor) |
800 mg twice daily for 8 days | 5-mg Single Dose | –13% | +1% | No SAPHRIS dose adjustment required |
| Carbamazepine (CYP3A4 inducer) |
400 mg twice daily for 15 days |
5-mg Single Dose | –16% | –16% | No SAPHRIS dose adjustment required |
| Valproate (UGT1A4 inhibitor) |
500 mg twice daily for 9 days | 5-mg Single Dose | 2% | –1% | No SAPHRIS dose adjustment required |
| AED Coadministered | Dose of AED (mg/day) |
Oxcarbazepine Dose (mg/day) |
Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval) |
Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval) |
|---|---|---|---|---|
| Carbamazepine | 400-2000 | 900 | nc |
40% decrease [CI: 17% decrease, 57% decrease] |
| Phenobarbital | 100-150 | 600-1800 | 14% increase [CI: 2% increase, 24% increase] |
25% decrease [CI: 12% decrease, 51% decrease] |
| Phenytoin | 250-500 | 600-1800 >1200-2400 |
nc up to 40% increase [CI: 12% increase, 60% increase] |
30% decrease [CI: 3% decrease, 48% decrease] |
| Valproic acid | 400-2800 | 600-1800 | nc |
18% decrease [CI: 13% decrease, 40% decrease] |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine | Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide | ↓ lamotrigine | Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels. | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine | Increased lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. | |
|
|
||
| albuterol, | famotidine | nizatidine |
| systemic and inhaled | felodipine | norfloxacin |
| amoxicillin | finasteride | ofloxacin |
| ampicillin, | hydrocortisone | omeprazole |
| with or without | isoflurane | prednisone, prednisolone |
| sulbactam | isoniazid | ranitidine |
| atenolol | isradipine | rifabutin |
| azithromycin | influenza vaccine | roxithromycin |
| caffeine, | ketoconazole | sorbitol |
| dietary digestion | lomefloxacin | (purgative doses do not |
| cefaclor | mebendazole | inhibit theophylline |
| co-trimoxazole | medroxyprogesterone | absorption) |
| (trimethoprim and | methylprednisolone | sucralfate |
| sulfamethoxazole) | metronidazole | terbutaline, systemic |
| diltiazem | metoprolol | terfenadine |
| dirithromycin | nadolol | tetracycline |
| enflurane | nifedipine | tocainide |
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) | Do not exceed 40 mg atorvastatin daily |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine | Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide |
|
|
| ? CBZ epoxide | May increase CBZ epoxide levels | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) |
|
Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate |
|
|
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
| Interacting Agents | Prescribing Recommendations |
| Strong CYP3A4 inhibitors (e.g.,Itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone |
Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine |
Do not exceed 20 mg simvastatin daily |
| Grapefruit juice |
Avoid grapefruit juice |
| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
|
|---|---|
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) | Do not exceed 40 mg atorvastatin daily |
|
|
|
|
|
Avoid atorvastatin
|
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
|
|
Do not exceed 20 mg atorvastatin daily
|
| HIV protease inhibitor (nelfinavir) | Do not exceed 40 mg atorvastatin daily |
| Enzyme | Inhibitors | Inducers |
|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
| Drug Class | Specific Drugs |
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
|
|
| ↓levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide |
|
|
| ? CBZ epoxide | May increase CBZ epoxide levels | |
| Phenobarbital/Primidone |
|
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) |
|
Decreased lamotrigine concentration approximately 40%. |
| Rifampin |
|
Decreased lamotrigine AUC approximately 40%. |
| Valproate |
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| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
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Multivalent cation-containing products including antacids, metal cation or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. |
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Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding |
|
Antidiabetic agent |
Carefully monitor blood glucose ( |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
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| Amiodarone Iodide (including iodine- containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
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| Interacting Agents | Prescribing Recommendations |
|---|---|
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
| Concomitant Drug Class: Drug Name |
Effect on Concentration of Etravirine or Concomitant Drug | Clinical Comment |
|---|---|---|
| ↑ = increase, ↓ = decrease, ↔ = no change | ||
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| efavirenz nevirapine |
↓ etravirine | Combining two NNRTIs has not been shown to be beneficial. Concomitant use of INTELENCE® with efavirenz or nevirapine may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and other NNRTIs should not be co-administered. |
| delavirdine | ↑ etravirine | Combining two NNRTIs has not been shown to be beneficial. INTELENCE® and delavirdine should not be co-administered. |
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| atazanavir (without ritonavir) |
↓ atazanavir | Concomitant use of INTELENCE® with atazanavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of atazanavir. INTELENCE® should not be co-administered with atazanavir without low-dose ritonavir. |
| atazanavir/ritonavir |
↓ atazanavir ↑ etravirine |
Concomitant use of INTELENCE® with atazanavir/ritonavir may cause a significant decrease in atazanavir Cmin and loss of therapeutic effect of atazanavir. In addition, the mean systemic exposure (AUC) of etravirine after co-administration of INTELENCE® with atazanavir/ritonavir is anticipated to be higher than the mean systemic exposure of etravirine observed in the Phase 3 trials after co-administration of INTELENCE® and darunavir/ritonavir (as part of the background regimen). INTELENCE® and atazanavir/ritonavir should not be co-administered. |
| darunavir/ritonavir |
↓ etravirine | The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE® was co-administered with darunavir/ritonavir. Because all subjects in the Phase 3 trials received darunavir/ritonavir as part of the background regimen and etravirine exposures from these trials were determined to be safe and effective, INTELENCE® and darunavir/ritonavir can be co-administered without dose adjustments. |
| fosamprenavir (without ritonavir) |
↑ amprenavir | Concomitant use of INTELENCE® with fosamprenavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of amprenavir. INTELENCE® should not be co-administered with fosamprenavir without low-dose ritonavir. |
| fosamprenavir/ritonavir |
↑ amprenavir | Due to a significant increase in the systemic exposure of amprenavir, the appropriate doses of the combination of INTELENCE® and fosamprenavir/ritonavir have not been established. INTELENCE® and fosamprenavir/ritonavir should not be co-administered. |
| indinavir (without ritonavir) |
↓ indinavir | Concomitant use of INTELENCE® with indinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of indinavir. INTELENCE® should not be co-administered with indinavir without low-dose ritonavir. |
| lopinavir/ritonavir |
↓ etravirine | The mean systemic exposure (AUC) of etravirine was reduced after co-administration of INTELENCE® with lopinavir/ritonavir (tablet). Because the reduction in the mean systemic exposures of etravirine in the presence of lopinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE® and lopinavir/ritonavir can be co-administered without dose adjustments. |
| nelfinavir (without ritonavir) |
↑ nelfinavir | Concomitant use of INTELENCE® with nelfinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of nelfinavir. INTELENCE® should not be co-administered with nelfinavir without low-dose ritonavir. |
| ritonavir |
↓ etravirine | Concomitant use of INTELENCE® with ritonavir 600 mg b.i.d. may cause a significant decrease in the plasma concentration of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and ritonavir 600 mg b.i.d. should not be co-administered. |
| saquinavir/ritonavir |
↓ etravirine | The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE® was co-administered with saquinavir/ritonavir. Because the reduction in the mean systemic exposures of etravirine in the presence of saquinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE® and saquinavir/ritonavir can be co-administered without dose adjustments. |
| tipranavir/ritonavir |
↓ etravirine | Concomitant use of INTELENCE® with tipranavir/ritonavir may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and tipranavir/ritonavir should not be co-administered. |
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| maraviroc |
↔ etravirine ↓ maraviroc |
When INTELENCE® is co-administered with maraviroc in the absence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 600 mg b.i.d. No dose adjustment of INTELENCE® is needed. |
| maraviroc/darunavir/ritonavir |
↔ etravirine ↑ maraviroc |
When INTELENCE® is co-administered with maraviroc in the presence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 150 mg b.i.d. No dose adjustment of INTELENCE® is needed. |
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digoxin |
↔ etravirine ↑ digoxin |
For patients who are initiating a combination of INTELENCE® and digoxin, the lowest dose of digoxin should initially be prescribed. For patients on a stable digoxin regimen and initiating INTELENCE®, no dose adjustment of either INTELENCE® or digoxin is needed. The serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect. |
| amiodarone, bepridil, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine |
↓ antiarrhythmics | Concentrations of these antiarrhythmics may be decreased when co-administered with INTELENCE®. INTELENCE® and antiarrhythmics should be co-administered with caution. Drug concentration monitoring is recommended, if available. |
|
warfarin |
↑ anticoagulants | Warfarin concentrations may be increased when co-administered with INTELENCE®. The international normalized ratio (INR) should be monitored when warfarin is combined with INTELENCE®. |
|
carbamazepine, phenobarbital, phenytoin |
↓ etravirine | Carbamazepine, phenobarbital and phenytoin are inducers of CYP450 enzymes. INTELENCE® should not be used in combination with carbamazepine, phenobarbital, or phenytoin as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®. |
|
fluconazole voriconazole |
↑ etravirine ↔ fluconazole ↑ voriconazole |
Co-administration of etravirine and fluconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and fluconazole should be co-administered with caution. No dose adjustment of INTELENCE® or fluconazole is needed. |
| Co-administration of etravirine and voriconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and voriconazole should be co-administered with caution. No dose adjustment of INTELENCE® or voriconazole is needed. | ||
|
itraconazole, ketoconazole, posaconazole |
↑ etravirine ↓ itraconazole ↓ ketoconazole ↔ posaconazole |
Posaconazole, a potent inhibitor of CYP3A4, may increase plasma concentrations of etravirine. Itraconazole and ketoconazole are potent inhibitors as well as substrates of CYP3A4. Concomitant systemic use of itraconazole or ketoconazole and INTELENCE® may increase plasma concentrations of etravirine. Simultaneously, plasma concentrations of itraconazole or ketoconazole may be decreased by INTELENCE®. Dose adjustments for itraconazole, ketoconazole or posaconazole may be necessary depending on the other co-administered drugs. |
|
clarithromycin |
↑ etravirine ↓ clarithromycin ↑ 14-OH-clarithromycin |
Clarithromycin exposure was decreased by INTELENCE®; however, concentrations of the active metabolite, 14-hydroxy-clarithromycin, were increased. Because 14-hydroxy-clarithromycin has reduced activity against |
|
rifampin, rifapentine |
↓ etravirine | Rifampin and rifapentine are potent inducers of CYP450 enzymes. INTELENCE® should not be used with rifampin or rifapentine as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®. |
|
rifabutin |
↓ etravirine ↓ rifabutin ↓ 25- |
If INTELENCE® is NOT co-administered with a protease inhibitor/ritonavir, then rifabutin at a dose of 300 mg q.d. is recommended. If INTELENCE® is co-administered with darunavir/ritonavir, lopinavir/ritonavir or saquinavir/ritonavir, then rifabutin should not be co-administered due to the potential for significant reductions in etravirine exposure. |
|
diazepam |
↑ diazepam | Concomitant use of INTELENCE® with diazepam may increase plasma concentrations of diazepam. A decrease in diazepam dose may be needed. |
|
dexamethasone (systemic) |
↓ etravirine | Systemic dexamethasone induces CYP3A and can decrease etravirine plasma concentrations. This may result in loss of therapeutic effect of INTELENCE®. Systemic dexamethasone should be used with caution or alternatives should be considered, particularly for long-term use. |
|
St. John's wort ( |
↓ etravirine | Concomitant use of INTELENCE® with products containing St. John's wort may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®. INTELENCE® and products containing St. John's wort should not be co-administered. |
|
atorvastatin fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin |
↔ etravirine ↓ atorvastatin ↑ 2-OH-atorvastatin ↔ etravirine ↑ fluvastatin, ↓ lovastatin, ↔ pravastatin, ↔ rosuvastatin, ↓ simvastatin |
The combination of INTELENCE® and atorvastatin can be given without dose adjustments, however, the dose of atorvastatin may need to be altered based on clinical response. No interaction between pravastatin, rosuvastatin and INTELENCE® is expected. Lovastatin and simvastatin are CYP3A substrates and co-administration with INTELENCE® may result in lower plasma concentrations of the HMG-CoA reductase inhibitor. Fluvastatin is metabolized by CYP2C9 and co-administration with INTELENCE® may result in higher plasma concentrations of the HMG-CoA reductase inhibitor. Dose adjustments for these HMG-CoA reductase inhibitors may be necessary. |
|
cyclosporine, sirolimus, tacrolimus |
↓ immunosuppressant | INTELENCE® and systemic immunosuppressants should be co-administered with caution because plasma concentrations of cyclosporine, sirolimus, or tacrolimus may be affected. |
|
methadone |
↔ etravirine ↔ methadone |
INTELENCE® and methadone can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as methadone maintenance therapy may need to be adjusted in some patients. |
|
sildenafil vardenafil, tadalafil |
↓ sildenafil ↓ N-desmethyl-sildenafil |
INTELENCE® and sildenafil can be co-administered without dose adjustments, however, the dose of sildenafil may need to be altered based on clinical effect. |
|
clopidogrel |
↓ clopidogrel (active) metabolite | Activation of clopidogrel to its active metabolite may be decreased when clopidogrel is co-administered with INTELENCE®. Alternatives to clopidogrel should be considered. |
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| Digoxin Serum Concentration Increase | Digoxin AUC Increase |
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| Amiodarone | 70% | NA | Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin dose by approximately 30% to 50% and continue monitoring. |
| Captopril | 58% | 39% | |
| Nitrendipine | 57% | 15% | |
| Propafenone | 35-85% | NA | |
| Quinidine | 100% | NA | |
| Ranolazine | 87% | 88% | |
| Ritonavir | NA | 86% | |
| Verapamil | 50-75% | NA | |
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| Carvedilol | 16% | 14% | Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin dose by approximately 15% to 30% and continue monitoring. |
| Diltiazem | 20% | NA | |
| Nifedipine | 45% | NA | |
| Rabeprazole | 29% | 19% | |
| Telmisartan | 20% | NA | |
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| Alprazolam, Azithromycin, Clarithromycin, Cyclosporine, Diclofenac, Diphenoxylate, Epoprostenol, Erythromycin, Esomeprazole, Indomethacin, Itraconazole, Ketoconazole, Lansoprazole, Metformin, Omeprazole, Propantheline, Spironolactone, Tetracycline | Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary. | ||
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Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20% to 40% as necessary. | ||
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| Please refer to section 12.3 for a complete list of drugs which were studied but reported no significant changes on digoxin exposure. | No additional actions are required. | ||
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Dofetilide | Concomitant administration with digoxin was associated with a higher rate of torsades de pointes. |
| Moricizine | Reported to increase PR interval and QRS duration. There are reports of first degree atrioventricular block or bundle branch block developing with digitalis administration. The known effects of moricizine on calcium conductance may explain the effects on atrioventricular node conduction. | |
| Sotalol | Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin. | |
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Teriparatide | Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium. |
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Thyroid | Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin. |
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Epinepherine | Can increase the risk of cardiac arrhythmias. |
| Norepinephrine | ||
| Dopamine | ||
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Succinylcholine | May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin. |
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Calcium | If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients. |
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| Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Amiodarone, verapamil, diltiazem | Do not exceed 10 mg simvastatin daily |
| Amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (> 1 quart daily) |
| Coadministered Drug | Dosing Schedule | Effect on Active Moiety (Risperidone + 9- Hydroxy-Risperidone(Ratio*) | Risperidone DoseRecommendation | ||
| Coadministered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6)Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 mg twicedaily | 1.4 | 1.5 | Re-evaluate dosing. Donot exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Donot exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A)Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four timesdaily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
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Coadministered |
(mg/day) |
(mg/day) |
Concentration (Mean Change, 90% Confidence Interval) |
AED on MHD Concentration (Mean Change, |
| Carbamazepine | 400-2000 | 900 | nc1 | 40% decrease [CI: 17% decrease, 57% decrease] |
| Phenobarbital | 100-150 | 600-1800 | 14% increase [CI: 2% increase, 24% increase] |
25% decrease [CI: 12% decrease, 51% decrease] |
| Phenytoin | 250-500 | 600-1800 >1200-2400 |
nc1,2
up to 40% increase3 [CI: 12% increase, 60% increase] |
30% decrease [CI: 3% decrease, 48% decrease] |
| Valproic acid | 400-2800 | 600-1800 | nc1 | 18% decrease [CI: 13% decrease, 40% decrease] |
| Coadministered Drug | Dosing Schedule | Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio |
Risperidone Dose Recommendation | ||
|---|---|---|---|---|---|
| Coadministered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6) Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 mg twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/ PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient's usual dose |
| Enzyme (CYP3A) Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
| Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) | VIAGRA 25 mg |
|---|---|
| Supine | 7.4 (-0.9, 15.7) |
| Standing | 6.0 (-0.8, 12.8) |
|
|
|
|
|
|
|
|
| Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) | VIAGRA 100 mg |
|---|---|
| Supine | 7.9 (4.6, 11.1) |
| Standing |
4.3 (-1.8,10.3) |
|
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|
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|
|
|
| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
|
|
|
| Amiodarone Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
|
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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| Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
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|
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
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3 mg twice daily |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone Iodide (including iodine- containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
|
|
|||
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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||
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||
| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
|
|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
|
|
|||
|
|
|||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
|
|
|||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
|
|
|||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
|
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+82% |
|
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|
+135% |
|
| AED Coadministered | AED Concentration | Topiramate Concentration |
| Phenytoin | NC or 25% increase |
48% decrease |
| Carbamazepine (CBZ) | NC | 40% decrease |
| CBZ epoxide |
NC | NE |
| Valproic acid | 11% decrease | 14% decrease |
| Phenobarbital | NC | NE |
| Primidone | NC | NE |
| Lamotrigine | NC at TPM doses up to 400 mg/day | 13% decrease |
| Interacting Drug | Interaction |
|---|---|
| Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents). | QUALAQUIN prolongs QT interval, ECG abnormalities including QT prolongation and Torsades de Pointes. Avoid concomitant use ( |
| Other antimalarials (e.g., halofantrine, mefloquine). | ECG abnormalities including QT prolongation. Avoid concomitant use ( |
| CYP3A4 inducers or inhibitors | Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine ( |
| CYP3A4 and CYP2D6 substrates | Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug ( |
| Digoxin | Increased digoxin plasma concentration ( |
|
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|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
|
|
|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
|
|
|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1) |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2) |
| Antidiabetic agents | Carefully monitor blood glucose (5.11, 7.3) |
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine | Do not exceed 10 mg atorvastatin daily |
| Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir) | Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used. |
| AED Co-administered | AED Concentration | TOPAMAX Concentration |
| NC = Less than 10% change in plasma concentration. NE = Not Evaluated |
||
| Phenytoin | NC or 25% increase |
48% decrease |
| Carbamazepine (CBZ) | NC | 40% decrease |
| CBZ epoxide |
NC | NE |
| Valproic acid | 11% decrease | 14% decrease |
| Phenobarbital | NC | NE |
| Primidone | NC | NE |
| Lamotrigine | NC at TPM doses up to 400 mg/day | 13% decrease |
| Interacting Agents | Prescribing Recommendations |
|---|---|
| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol | Contraindicated with JUVISYNC |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin (100 mg/10 mg or 50 mg/10 mg JUVISYNC) daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin (100 mg/20 mg or 50 mg/20 mg JUVISYNC) daily |
| Grapefruit juice | Avoid grapefruit juice |
| Concomitant Drug Class: Drug Name | Effect | Clinical Comment |
|---|---|---|
|
|
||
| Protease inhibitor: atazanavir |
↓atazanavir ↑ tenofovir |
Coadministration of atazanavir with ATRIPLA is not recommended. Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA. |
| Protease inhibitor: fosamprenavir calcium |
↓ amprenavir | Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and ATRIPLA with respect to safety and efficacy have not been established. Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when ATRIPLA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when ATRIPLA is administered with fosamprenavir plus ritonavir twice daily. |
| Protease inhibitor: indinavir |
↓ indinavir | The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz. |
| Protease inhibitor: lopinavir/ritonavir |
↓ lopinavir ↑ tenofovir |
Do not use once daily administration of lopinavir/ritonavir. Dose adjustment of lopinavir/ritonavir is recommended when coadministered with efavirenz. Refer to the full prescribing information for lopinavir/ritonavir for guidance on coadministration with efavirenz- or tenofovir-containing regimens, such as ATRIPLA. Patients should be monitored for tenofovir-associated adverse reactions. |
| Protease inhibitor: ritonavir |
↑ ritonavir ↑ efavirenz |
When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when ATRIPLA is used in combination with ritonavir. |
| Protease inhibitor: saquinavir |
↓ saquinavir | Appropriate doses of the combination of efavirenz and saquinavir/ritonavir with respect to safety and efficacy have not been established. |
| CCR5 co-receptor antagonist: maraviroc |
↓ maraviroc | Efavirenz decreases plasma concentrations of maraviroc. Refer to the full prescribing information for maraviroc for guidance on coadministration with ATRIPLA. |
| NRTI: didanosine |
↑ didanosine | Coadministration of ATRIPLA and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions including pancreatitis, lactic acidosis, and neuropathy. A dose reduction of didanosine is recommended when co-administered with tenofovir DF. For additional information on coadministration with tenofovir DF-containing products, please refer to the didanosine prescribing information. |
| NNRTI: Other NNRTIs |
↑ or ↓ efavirenz and/or NNRTI | Combining two NNRTIs has not been shown to be beneficial. ATRIPLA contains efavirenz and should not be coadministered with other NNRTIs. |
| Integrase strand transfer inhibitor: raltegravir |
↓ raltegravir | Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed. |
|
|
||
| Protease inhibitor: boceprevir |
↓ boceprevir | Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with efavirenz, which may result in loss of therapeutic effect. The combination should be avoided. |
| Protease inhibitor: telaprevir |
↓ telaprevir ↓ efavirenz |
Concomitant administration of telaprevir and efavirenz resulted in reduced steady-state exposures to telaprevir and efavirenz. |
|
|
||
| Anticoagulant: warfarin |
↑ or ↓ warfarin | Plasma concentrations and effects potentially increased or decreased by efavirenz. |
| Anticonvulsants: carbamazepine |
↓ carbamazepine ↓ efavirenz |
There are insufficient data to make a dose recommendation for ATRIPLA. Alternative anticonvulsant treatment should be used. |
| phenytoin phenobarbital |
↓ anticonvulsant ↓ efavirenz |
Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted. |
| Antidepressants: bupropion |
↓ buproprion | The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded. |
| sertraline | ↓ sertraline | Increases in sertraline dose should be guided by clinical response. |
| Antifungals: itraconazole |
↓ itraconazole ↓ hydroxy-itraconazole |
Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered. |
| ketoconazole | ↓ ketoconazole | Drug interaction trials with ATRIPLA and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole. |
| posaconazole | ↓ posaconazole | Avoid concomitant use unless the benefit outweighs the risks. |
| Anti-infective: clarithromycin |
↓ clarithromycin ↑ 14-OH metabolite |
Clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of ATRIPLA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with ATRIPLA. |
| Antimycobacterial: rifabutin |
↓ rifabutin concentration | Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week. |
| rifampin | ↓ efavirenz | If ATRIPLA is coadministered with rifampin to patients weighing 50 kg or more, an additional 200 mg/day of efavirenz is recommended. |
| Calcium channel blockers: diltiazem |
↓ diltiazem ↓ desacetyl diltiazem ↓ N-monodes-methyl diltiazem |
Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of ATRIPLA is necessary when administered with diltiazem. |
| Others (e.g., felodipine, nicardipine, nifedipine, verapamil) |
↓ calcium channel blocker | No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker). |
| HMG-CoA reductase inhibitors: atorvastatin pravastatin simvastatin |
↓ atorvastatin ↓ pravastatin ↓ simvastatin |
Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose. |
| Hormonal contraceptives: | ||
| Oral: ethinyl estradiol/norgestimate |
↓ active metabolites of norgestimate | A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed. |
| Implant: etonogestrel |
↓ etonogestrel | A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients. |
| Immunosuppressants: cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A |
↓ immuno-suppressant | Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by efavirenz. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with ATRIPLA. |
| Narcotic analgesic: methadone |
↓ methadone | Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms. |
| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
|
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine | Do not exceed 10 mg atorvastatin daily |
| Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir) | Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used. |
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| ↓ = Decreased (induces lamotrigine glucuronidation) |
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| ↑ = Increased (inhibits lamotrigine glucuronidation) |
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| ? = Conflicting data |
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| Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz*, nevirapine* |
↓ lopinavir | KALETRA dose increase is recommended in all patients Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz. KALETRA should not be administered once daily in combination with efavirenz or nevirapine |
| Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine |
↑ lopinavir | Appropriate doses of the combination with respect to safety and efficacy have not been established. |
| Nucleoside Reverse Transcriptase Inhibitor: didanosine |
KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food). |
|
| Nucleoside Reverse Transcriptase Inhibitor: tenofovir |
↑ tenofovir | KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir. |
| Nucleoside Reverse Transcriptase Inhibitor: abacavir zidovudine |
↓ abacavir ↓ zidovudine |
KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown. |
| HIV-1 Protease Inhibitor: amprenavir* |
↑ amprenavir ↓ lopinavir |
KALETRA should not be administered once daily in combination with amprenavir |
| HIV-1 Protease Inhibitor: fosamprenavir/ritonavir |
↓ amprenavir ↓ lopinavir |
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor: indinavir* |
↑ indinavir | Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily |
| HIV-1 Protease Inhibitor: nelfinavir* |
↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir |
KALETRA should not be administered once daily in combination with nelfinavir |
| HIV-1 Protease Inhibitor: ritonavir* |
↑ lopinavir | Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor: saquinavir* |
↑ saquinavir | The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir. |
| HIV-1 Protease Inhibitor: tipranavir |
↓ lopinavir AUC and Cmin | KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily). |
| HIV CCR5 – antagonist: maraviroc | ↑ maraviroc | Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry® (maraviroc). |
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| Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), and quinidine |
↑ antiarrhythmics | Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA. |
| Anticancer Agents: vincristine, vinblastine, dasatinib, nilotinib |
↑ anticancer agents | Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents. For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions. |
| Anticoagulant: warfarin |
Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored. | |
| Anticonvulsants: carbamazepine, phenobarbital, phenytoin |
↓ lopinavir ↓ phenytoin |
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA. |
| Antidepressant: bupropion |
↓ bupropion ↓ active metabolite, hydroxybupropion |
Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion. |
| Antidepressant: trazodone |
↑ trazodone | Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered. |
| Anti-infective: clarithromycin |
↑ clarithromycin | For patients with renal impairment, the following dosage adjustments should be considered:
No dose adjustment for patients with normal renal function is necessary. |
| Antifungals: ketoconazole*, itraconazole, voriconazole |
↑ ketoconazole ↑ itraconazole ↓ voriconazole |
High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended. Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients. |
| Anti-gout: colchicine |
↑ colchicine | Patients with renal or hepatic impairment should not be given colchicine with KALETRA. 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). |
| Antimycobacterial: rifabutin* |
↑ rifabutin and rifabutin metabolite | Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary. |
| Antimycobacterial: rifampin |
↓ lopinavir | May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone |
| Antiparasitic: atovaquone |
↓ atovaquone | Clinical significance is unknown; however, increase in atovaquone doses may be needed. |
| Benzodiazepines: parenterally administered midazolam | ↑ midazolam | Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam |
| Calcium Channel Blockers, dihydropyridine: e.g., felodipine, nifedipine, nicardipine |
↑ dihydropyridine calcium channel blockers | Caution is warranted and clinical monitoring of patients is recommended. |
| Contraceptive: ethinyl estradiol* |
↓ ethinyl estradiol | Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended. |
| Corticosteroid: dexamethasone |
↓ lopinavir | Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly. |
| disulfiram/metronidazole |
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| Endothelin receptor antagonists: bosentan |
↑ bosentan |
In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. |
| HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin |
↑ atorvastatin ↑ rosuvastatin |
Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with KALETRA. |
| Immunosuppressants: cyclosporine, tacrolimus, rapamycin |
↑ immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA. |
| Inhaled Steroid: fluticasone |
↑ fluticasone | Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect. |
| Long-acting beta-adrenoceptor agonist: salmeterol |
↑ salmeterol | Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
| Narcotic Analgesic: methadone* fentanyl |
↓ methadone ↑ fentanyl |
Dosage of methadone may need to be increased when co-administered with KALETRA. Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA. |
| PDE5 inhibitors: sildenafil, tadalafil, vardenafil |
↑ sildenafil ↑ tadalafil ↑ vardenafil |
Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA The following dose adjustments are recommended for use of tadalafil (Adcirca®) with KALETRA: In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: It is recommended not to exceed the following doses:
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| AED Co-administered | AED Concentration | Topiramate Concentration |
|---|---|---|
| NC = Less than 10% change in plasma concentration. NE = Not Evaluated |
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| Phenytoin | NC or 25% increase |
48% decrease |
| Carbamazepine (CBZ) | NC | 40% decrease |
| CBZ epoxide |
NC | NE |
| Valproic acid | 11% decrease | 14% decrease |
| Phenobarbital | NC | NE |
| Primidone | NC | NE |
| Lamotrigine | NC at TPM doses up to 400 mg/day | 13% decrease |
| Concomitant Drug |
Effect on Concentration of Lamotrigine or Concomitant Drug |
Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine ↓ levonorgestrel |
Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%. |
| Carbamazepine (CBZ) and CBZ epoxide |
↓ lamotrigine ? CBZ epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase CBZ epoxide levels |
| Phenobarbital/Primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40%. |
| Valproate |
↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
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| Antacids, sucralfate, multivitamins, and other products containing multivalent cations | Moxifloxacin absorption is decreased. Administer AVELOX Tablet at least 4 hours before or 8 hours after these products. ( |
| Warfarin | Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. ( |
| Class IA and Class III antiarrhythmics: | Proarrhythmic effect may be enhanced. Avoid concomitant use. ( |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine | Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide | ↓ lamotrigine | Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine | Increased lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
| ↑ Indicates increase. ↓ Indicates decrease. |
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| Drug | Effect | Clinical Comment |
| ganciclovir | ↑didanosine concentration | If there is no suitable alternative to ganciclovir, then use in combination with didanosine delayed-release capsules with caution. Monitor for didanosine-associated toxicity. |
| methadone | ↓didanosine concentration | If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is didanosine delayed-release capsules. Patients should be closely monitored for adequate clinical response when didanosine delayed-release capsules are coadministered with methadone, including monitoring for changes in HIV RNA viral load. Do not coadminister methadone with didanosine pediatric powder due to significant decreases in didanosine concentrations. |
| nelfinavir | No interaction 1 hour after didanosine | Administer nelfinavir 1 hour after didanosine delayed-release capsules. |
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↑didanosine concentration |
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| ↑ Indicates increase. | ||
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| Drugs that may cause pancreatic toxicity | ↑risk of pancreatitis | Use only with extreme caution. |
| Neurotoxic drugs | ↑risk of neuropathy | Use with caution. |
| Coadministered Drug |
Dosing Schedule |
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Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
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Risperidone Dose Recommendation |
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Coadministered Drug |
Risperidone |
AUC |
Cm
a
x
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| Enzyme (CYP2D6) Inhibitors |
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| Fluoxetine |
20 mg/day |
2 or 3 mg twice daily |
1.4 |
1.5 |
Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine |
10 mg/day |
4 mg/day |
1.3 |
- |
Re-evaluate dosing. |
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20 mg/day |
4 mg/day |
1.6 |
- |
Do not exceed 8 mg/day |
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40 mg/day |
4 mg/day |
1.8 |
- |
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| Enzyme (CYP3A/ PgP inducers) |
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| Carbamazepine |
573 ± 168 mg/day |
3 mg twice daily |
0.51 |
0.55 |
Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors |
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| Ranitidine |
150 mg twice daily |
1 mg single dose |
1.2 |
1.4 |
Dose adjustment not needed |
| Cimetidine |
400 mg twice daily |
1 mg single dose |
1.1 |
1.3 |
Dose adjustment not needed |
| Erythromycin |
500 mg four times daily |
1 mg single dose |
1.1 |
0.94 |
Dose adjustment not needed |
| Other Drugs |
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| Amitriptyline |
50 mg twice daily |
3 mg twice daily |
1.2 |
1.1 |
Dose adjustment not needed |
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If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once a day. |
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| Strong CYP3A4 Inhibitors, (e.g., itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol |
Contraindicated with VYTORIN |
| Verapamil, diltiazem | Do not exceed 10/10 mg VYTORIN daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 10/20 mg VYTORIN daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
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| Carbamazepine | 400 to 2000 | 900 | nc1 | 40% decrease [CI: 17% decrease, 57% decrease] |
| Phenobarbital | 100 to 150 | 600 to 1800 | 14% increase [CI: 2% increase, 24% increase] |
25% decrease [CI: 12% decrease, 51% decrease] |
| Phenytoin | 250 to 500 | 600 to 1800 >1200 to 2400 | nc1,2
up to 40% increase3 [CI: 12% increase, 60% increase] |
30% decrease [CI: 3% decrease, 48% decrease] |
| Valproic acid | 400 to 2800 | 600 to 1800 | nc1 | 18% decrease [CI: 13% decrease, 40% decrease] |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine | Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide | ↓ lamotrigine | Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine | Increased lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
| Coadministered Drug |
Dosing Schedule |
|
Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
|
Risperidone Dose Recommendation |
|
|
Coadministered Drug |
Risperidone |
AUC |
Cm
a
x
|
|
| Enzyme (CYP2D6) Inhibitors |
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|
| Fluoxetine |
20 mg/day |
2 or 3 mg twice daily |
1.4 |
1.5 |
Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine |
10 mg/day |
4 mg/day |
1.3 |
- |
Re-evaluate dosing. |
|
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20 mg/day |
4 mg/day |
1.6 |
- |
Do not exceed 8 mg/day |
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40 mg/day |
4 mg/day |
1.8 |
- |
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| Enzyme (CYP3A/ PgP inducers) |
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| Carbamazepine |
573 ± 168 mg/day |
3 mg twice daily |
0.51 |
0.55 |
Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors |
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| Ranitidine |
150 mg twice daily |
1 mg single dose |
1.2 |
1.4 |
Dose adjustment not needed |
| Cimetidine |
400 mg twice daily |
1 mg single dose |
1.1 |
1.3 |
Dose adjustment not needed |
| Erythromycin |
500 mg four times daily |
1 mg single dose |
1.1 |
0.94 |
Dose adjustment not needed |
| Other Drugs |
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| Amitriptyline |
50 mg twice daily |
3 mg twice daily |
1.2 |
1.1 |
Dose adjustment not needed |
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| Interacting Agents | Prescribing Recommendations |
| Cyclosporine | Do not exceed 10 mg atorvastatin daily |
| Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir) | Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used. |
| *Refer to |
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| albuterol, systemic and inhaled | felodipinefinasteride | nizatidinenorfloxacin | |
| amoxicillin | hydrocortisone | ofloxacin | |
| ampicillin, with or without sulbactam | isoflurane isoniazid | omeprazole prednisone, prednisolone | |
| atenolol | isradipine | ranitidine | |
| azithromycin | influenza vaccine | rifabutin | |
| caffeine, dietary ingestion | ketoconazo lelomefloxacin | roxithromycin sorbitol | |
| cefaclor | mebendazole | (purgative doses do not | |
| co-trimoxazole (trimethoprim and sulfamethoxazole) | medroxyprogesteronemethylprednisolone | inhibit theophylline absorption) | |
| diltiazem | metronidazole | sucralfate | |
| dirithromycin | metoprolol | terbutaline, systemic | |
| enflurane | nadolol | terfenadine | |
| famotidine | nifedipine | tetracycline | |
| tocainide | |||
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| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
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| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
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| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine, danazol | Do not exceed 10 mg simvastatin daily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (> 1 quart daily) |
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| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
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Drug Name |
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| HIV Protease Inhibitor: atazanavir |
When co-administered with reduced doses of atazanavir and ritonavir ↑ atazanavir (↑ AUC, ↑ Cmax, ↑ Cmin) |
Atazanavir plasma concentrations achieved with atazanavir 300 mg once daily and ritonavir 100 mg once daily are higher than those achieved with atazanavir 400 mg once daily. See the complete prescribing information for Reyataz® (atazanavir) for details on co-administration of atazanavir 300 mg once daily with ritonavir 100 mg once daily. |
| HIV Protease Inhibitor: darunavir |
When co-administered with reduced doses of ritonavir ↑ darunavir (↑ AUC, ↑ Cmax, ↑ Cmin) |
See the complete prescribing information for Prezista® (darunavir) for details on co-administration of darunavir 600 mg twice daily with ritonavir 100 mg twice daily or darunavir 800 mg once daily with ritonavir 100 mg once daily. |
| HIV Protease Inhibitor: fosamprenavir |
When co-administered with reduced doses of ritonavir ↑ amprenavir (↑ AUC, ↑ Cmax, ↑ Cmin) |
See the complete prescribing information for Lexiva® (fosamprenavir) for details on co-administration of fosamprenavir 700 mg twice daily with ritonavir 100 mg twice daily, fosamprenavir 1400 mg once daily with ritonavir 200 mg once daily or fosamprenavir 1400 mg once daily with ritonavir 100 mg once daily. |
| HIV Protease Inhibitor: indinavir |
When co-administered with reduced doses of indinavir and ritonavir ↑ indinavir (↔ AUC, ↓ Cmax, ↑ Cmin) |
Alterations in concentrations are noted when reduced doses of indinavir are co-administered with NORVIR. Appropriate doses for this combination, with respect to efficacy and safety, have not been established. |
| HIV Protease Inhibitor: saquinavir |
When co-administered with reduced doses of ritonavir ↑ saquinavir (↑ AUC, ↑ Cmax, ↑ Cmin) |
See the complete prescribing information for Invirase® (saquinavir) for details on co-administration of saquinavir 1000 mg twice daily with ritonavir 100 mg twice daily. Saquinavir/ritonavir should not be given together with rifampin, due to the risk of severe hepatotoxicity (presenting as increased hepatic transaminases) if the three drugs are given together. |
| HIV Protease Inhibitor: tipranavir |
When co-administered with reduced doses of ritonavir ↑ tipranavir (↑ AUC, ↑ Cmax, ↑ Cmin) |
See the complete prescribing information for Aptivus® (tipranavir) for details on co-administration of tipranavir 500 mg twice daily with ritonavir 200 mg twice daily. There have been reports of clinical hepatitis and hepatic decompensation including some fatalities. All patients should be followed closely with clinical and laboratory monitoring, especially those with chronic hepatitis B or C co-infection, as these patients have an increased risk of hepatotoxicity. Liver function tests should be performed prior to initiating therapy with tipranavir/ritonavir, and frequently throughout the duration of treatment. |
| Non-Nucleoside Reverse Transcriptase Inhibitor: delavirdine |
↑ ritonavir (↑AUC, ↑Cmax, ↑ Cmin) | Appropriate doses of this combination with respect to safety and efficacy have not been established. |
| HIV CCR5 – antagonist: maraviroc | ↑ maraviroc | Concurrent administration of maraviroc with ritonavir will increase plasma levels of maraviroc. For specific dosage adjustment recommendations, please refer to the complete prescribing information for Selzentry® (maraviroc). |
| Integrase Inhibitor: Raltegravir | ↓ raltegravir | The effects of ritonavir on raltegravir with ritonavir dosage regimens greater than 100 mg twice daily have not been evaluated, however raltegravir concentrations may be decreased with ritonavir coadministration. |
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| Analgesics, Narcotic: tramadol, propoxyphene |
A dose decrease may be needed for these drugs when co-administered with ritonavir. | |
| Anesthetic: meperidine |
↓ meperidine/ ↑ normeperidine (metabolite) | Dosage increase and long-term use of meperidine with ritonavir are not recommended due to the increased concentrations of the metabolite normeperidine which has both analgesic activity and CNS stimulant activity (e.g., seizures). |
| Antialcoholics: disulfiram/ metronidazole |
Ritonavir formulations contain alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole). | |
| Antiarrhythmics: disopyramide, lidocaine, mexiletine |
↑ antiarrhythmics | Caution is warranted and therapeutic concentration monitoring is recommended for antiarrhythmics when co-administered with ritonavir, if available. |
| Anticancer Agents: dasatinib, nilotinib, vincristine, vinblastine |
↑ anticancer agents | Concentrations of these drugs may be increased when co-administered with ritonavir resulting in the potential for increased adverse events usually associated with these anticancer agents. For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when ritonavir is administered concurrently with vincristine or vinblastine. Clinicians should be aware that if the ritonavir containing regimen is withheld for a prolonged period, consideration should be given to altering the regimen to not include a CYP3A or P-gp inhibitor in order to control HIV-1 viral load. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as NORVIR. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions. |
| Anticoagulant: warfarin |
↓ R-warfarin ↓↑ S-warfarin |
Initial frequent monitoring of the INR during ritonavir and warfarin co-administration is indicated. |
| Anticoagulant: rivaroxaban |
↑ rivaroxaban | Avoid concomitant use of rivaroxaban and ritonavir. Co-administration of ritonavir and rivaroxaban is expected to result in increased exposure of rivaroxaban which may lead to risk of increased bleeding. |
| Anticonvulsants: carbamazepine, clonazepam, ethosuximide |
↑ anticonvulsants | Use with caution. A dose decrease may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available. |
| Anticonvulsants: divalproex, lamotrigine, phenytoin |
↓ anticonvulsants | Use with caution. A dose increase may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available. |
| Antidepressants: nefazodone, selective serotonin reuptake inhibitors (SSRIs): e.g. fluoxetine, paroxetine, tricyclics: e.g. amitriptyline, nortriptyline |
↑ antidepressants | A dose decrease may be needed for these drugs when co-administered with ritonavir. |
| Antidepressant: bupropion |
↓ bupropion ↓ active metabolite, hydroxybupropion |
Concurrent administration of bupropion with ritonavir may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving ritonavir and bupropion concurrently should be monitored for an adequate clinical response to bupropion. |
| Antidepressant: desipramine |
↑ desipramine | Dosage reduction and concentration monitoring of desipramine is recommended. |
| Antidepressant: trazodone | ↑ trazodone | Concomitant use of trazodone and NORVIR increases plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and NORVIR. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered. |
| Antiemetic: dronabinol |
↑ dronabinol | A dose decrease of dronabinol may be needed when co-administered with ritonavir. |
| Antifungal: ketoconazole itraconazole voriconazole |
↑ ketoconazole ↑ itraconazole ↓ voriconazole |
High doses of ketoconazole or itraconazole (greater than 200 mg per day) are not recommended. Co-administration of voriconazole and ritonavir doses of 400 mg every 12 hours or greater is contraindicated. Co-administration of voriconazole and ritonavir 100 mg should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. |
| Anti-gout: colchicine |
↑ colchicine | Patients with renal or hepatic impairment should not be given colchicine with ritonavir. 0.6 mg (one tablet) for one dose, followed by 0.3 mg (half tablet) one hour later. Dose to be repeated no earlier than three days. If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). |
| Anti-infective: clarithromycin |
↑ clarithromycin | For patients with renal impairment the following dosage adjustments should be considered:
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| Antimycobacterial: rifabutin |
↑ rifabutin and rifabutin metabolite | Dosage reduction of rifabutin by at least three-quarters of the usual dose of 300 mg per day is recommended (e.g., 150 mg every other day or three times a week). Further dosage reduction may be necessary. |
| Antimycobacterial: rifampin |
↓ ritonavir | May lead to loss of virologic response. Alternate antimycobacterial agents such as rifabutin should be considered (see Antimycobacterial: rifabutin, for dose reduction recommendations). |
| Antiparasitic: atovaquone |
↓ atovaquone | Clinical significance is unknown; however, increase in atovaquone dose may be needed. |
| Antiparasitic: quinine |
↑ quinine | A dose decrease of quinine may be needed when co-administered with ritonavir. |
| β-Blockers: metoprolol, timolol |
↑ Beta-Blockers | Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with ritonavir. |
| Bronchodilator: theophylline |
↓ theophylline | Increased dosage of theophylline may be required; therapeutic monitoring should be considered. |
| Calcium channel blockers: diltiazem, nifedipine, verapamil |
↑ calcium channel blockers | Caution is warranted and clinical monitoring of patients is recommended.A dose decrease may be needed for these drugs when co-administered with ritonavir. |
| Digoxin | ↑ digoxin | Concomitant administration of ritonavir with digoxin may increase digoxin levels. Caution should be exercised when co-administering ritonavir with digoxin, with appropriate monitoring of serum digoxin levels. |
| Endothelin receptor antagonists: bosentan | ↑ bosentan |
In patients who have been receiving ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of ritonavir. After at least 10 days following the initiation of ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. |
| HMG-CoA Reductase Inhibitor: atorvastatin rosuvastatin |
↑ atorvastatin ↑ rosuvastatin |
Titrate atorvastatin and rosuvastatin dose carefully and use the lowest necessary dose. If NORVIR is used with another protease inhibitor, see the complete prescribing information for the concomitant protease inhibitor for details on co-administration with atorvastatin and rosuvastatin. |
| Immunosuppressants: cyclosporine, tacrolimus, sirolimus (rapamycin) |
↑ immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with ritonavir. |
| Inhaled or Intranasal Steroid e.g.: Fluticasone Budesonide |
↑ glucocorticoids | Concomitant use of ritonavir and fluticasone or other glucocorticoids that are metabolized by CYP3A is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. Concomitant use may result in increased steroid concentrations and reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during postmarketing use in patients when ritonavir has been coadministered with fluticasone propionate or budesonide. |
| Long-acting beta-adrenoceptor agonist: salmeterol | ↑ salmeterol | Concurrent administration of salmeterol and ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
| Narcotic Analgesic: methadone fentanyl |
↓ methadone ↑ fentanyl |
Dosage increase of methadone may be considered. Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with NORVIR. |
| Neuroleptics: perphenazine, risperidone, thioridazine |
↑ neuroleptics | A dose decrease may be needed for these drugs when co-administered with ritonavir. |
| Oral Contraceptives or Patch Contraceptives: ethinyl estradiol |
↓ ethinyl estradiol | Alternate methods of contraception should be considered. |
| PDE5 Inhibitors: avanafil sildenafil, tadalafil, vardenafil |
↑ avanafil ↑ sildenafil ↑ tadalafil ↑ vardenafil |
Do not use ritonavir with avanafil because a safe and effective avanafil dosage regimen has not been established. Particular caution should be used when prescribing sildenafil, tadalafil or vardenafil in patients receiving ritonavir. Coadministration of ritonavir with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse events, including hypotension, syncope, visual changes, and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with ritonavir The following dose adjustments are recommended for use of tadalafil (AdcircaTM) with ritonavir: In patients receiving ritonavir for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Avoid use of ADCIRCA during the initiation of ritonavir. Stop ADCIRCA at least 24 hours prior to starting ritonavir. After at least one week following the initiation of ritonavir, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for the treatment of erectile dysfunction: It is recommended not to exceed the following doses:
Use with increased monitoring for adverse events. |
| Sedative/hypnotics: buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem |
↑ sedative/hypnotics | A dose decrease may be needed for these drugs when co-administered with ritonavir. |
| Sedative/hypnotics: Parenteral midazolam |
↑ midazolam | Co-administration of oral midazolam with NORVIR is CONTRAINDICATED. Concomitant use of parenteral midazolam with NORVIR may increase plasma concentrations of midazolam. Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. |
| Steroids (systemic) e.g.: budesonide, dexamethasone, prednisone | ↑ glucocorticoids | Concomitant use of glucocorticoids that are metabolized by CYP3A is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. Concomitant use may result in increased steroid concentrations and reduced serum cortisol concentrations. This may increase the risk for development of systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression. |
| Stimulant: methamphetamine |
↑ methamphetamine | Use with caution. A dose decrease of methamphetamine may be needed when co-administered with ritonavir. |
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Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
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Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
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Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function. |
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Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4 . Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
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Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
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Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
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- Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
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- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
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- Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
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- Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
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- Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
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- (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
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Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
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| Erythromycin (500 mg every 8 hrs) | +82% | +109% |
| Ketoconazole (400 mg once daily) | +135% | +164% |
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine | Do not exceed 10 mg atorvastatin daily |
| Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir) | Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used. |
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| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine, danazol | Do not exceed 10 mg simvastatin daily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Diltiazem | Do not exceed 40 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
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| ciprofloxacin | melphalan | azapropazon | cimetidine |
| gentamicin | colchicine | ranitidine | |
| tobramycin |
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diclofenac | |
| vancomycin | amphotericin B | naproxen |
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| trimethoprim with sulfamethoxazole | ketoconazole | sulindac | tacrolimus |
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| fibric acid derivatives (e.g.,bezafibrate, fenofibrate) |
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| methotrexate |
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| diltiazem | fluconazole | azithromycin | methylprednisolone | allopurinol |
| nicardipine | itraconazole | clarithromycin | amiodarone | |
| verapamil | ketoconazole | erythromycin | bromocriptine | |
| voriconazole | quinupristin/ | colchicine | ||
| dalfopristin | danazol | |||
| imatinib | ||||
| metoclopramide | ||||
| nefazodone | ||||
| oral contraceptives |
|
|
|
|
| nafcillin | carbamazepine | bosentan |
| rifampin | oxcarbazepine | octreotide |
| phenobarbital | orlistat | |
| phenytoin | sulfinpyrazone | |
| St. John's Wort | ||
| terbinafine | ||
| ticlopidine |
| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
|
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine | Do not exceed 10 mg atorvastatin daily |
| Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir) | Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used. |
| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
|
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) | Do not exceed 40 mg atorvastatin daily |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
|
Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide |
|
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels. | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate |
|
Increased lamotrigine concentrations slightly more than 2 fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
|
|
|||||
| Coadministered Drug |
Dosing Schedule |
|
Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
|
Risperidone Dose Recommendation |
|
|
Coadministered Drug |
Risperidone |
AUC |
Cm
a
x
|
|
| Enzyme (CYP2D6) Inhibitors |
|
|
|
|
|
| Fluoxetine |
20 mg/day |
2 or 3 mg twice daily |
1.4 |
1.5 |
Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine |
10 mg/day |
4 mg/day |
1.3 |
- |
Re-evaluate dosing. |
|
|
|
|
|
|
|
|
|
20 mg/day |
4 mg/day |
1.6 |
- |
Do not exceed 8 mg/day |
|
|
40 mg/day |
4 mg/day |
1.8 |
- |
|
| Enzyme (CYP3A/ PgP inducers) inducers |
|
|
|
|
|
| Carbamazepine |
573 ± 168 mg/day |
3 mg twice daily |
0.51 |
0.55 |
Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors |
|
|
|
|
|
| Ranitidine |
150 mg twice daily |
1 mg single dose |
1.2 |
1.4 |
Dose adjustment not needed |
| Cimetidine |
400 mg twice daily |
1 mg single dose |
1.1 |
1.3 |
Dose adjustment not needed |
| Erythromycin |
500 mg four times daily |
1 mg single dose |
1.1 |
0.94 |
Dose adjustment not needed |
| Other Drugs |
|
|
|
|
|
| Amitriptyline |
50 mg twice daily |
3 mg twice daily |
1.2 |
1.1 |
Dose adjustment not needed |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
| Drug Class: Drug Name | Clinical Comment |
|---|---|
| Anticonvulsant agents: phenytoin, phenobarbital, carbamazepine | May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of non-nucleoside reverse transcriptase inhibitors. |
| Antihistamines: astemizole, terfenadine | CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. |
| Antimycobacterials: rifabutin, | May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of non-nucleoside reverse transcriptase inhibitors or other coadministered antiviral agents. |
| Ergot Derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine | CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. |
| GI motility agent: cisapride | CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. |
| Herbal Products: St. John's wort (hypericum perforatum) | May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of non-nucleoside reverse transcriptase inhibitors. |
| HMG-CoA reductase inhibitors: lovastatin, simvastatin | Potential for serious reactions such as risk of myopathy including rhabdomyolysis. |
| Neuroleptic: pimozide | CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. |
| Sedative/hypnotics: alprazolam, midazolam, triazolam | CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression. |
| Concomitant Drug Class: Drug Name | Effect on Concentration of delavirdine or Concomitant Drug | Clinical Comment |
|---|---|---|
| ↑ Indicates increase | ||
| ↓ Indicates decrease | ||
| Amprenavir | ↑ Amprenavir | Appropriate doses of this combination, with respect to safety, efficacy and pharmacokinetics, have not been established. |
| Didanosine | ↓ Delavirdine ↓ Didanosine | Administration of didanosine (buffered tablets) and RESCRIPTOR should be separated by at least one hour. |
| Indinavir | ↑ Indinavir | A dose reduction of indinavir to 600 mg tid should be considered when RESCRIPTOR and indinavir are coadministered. |
| Lopinavir/Ritonavir | ↑ Lopinavir ↑ Ritonavir | Appropriate doses of this combination, with respect to safety, efficacy and pharmacokinetics, have not been established. |
| Nelfinavir | ↑ Nelfinavir ↓ Delavirdine | Appropriate doses of this combination, with respect to safety, efficacy and pharmacokinetics, have not been established. (See |
| Ritonavir | ↑Ritonavir | Appropriate doses of this combination, with respect to safety, efficacy and pharmacokinetics, have not been established. |
| Saquinavir | ↑ Saquinavir | A dose reduction of saquinavir (soft gelatin capsules) may be considered when RESCRIPTOR and saquinavir are coadministered. (See |
| Acid blockers: antacids H2Receptor antagonists: cimetidine, famotidine, nizatidine, ranitidine Proton pump inhibitors: omeprazole, lansoprazole | ↓ Delavirdine | Doses of an antacid and RESCRIPTOR should be separated by at least one hour, because the absorption of delavirdine is reduced when coadministered with antacids. |
| These agents increase gastric pH and may reduce the absorption of delavirdine. Although the effect of these drugs on delavirdine absorption has not been evaluated, chronic use of these drugs with RESCRIPTOR is not recommended. | ||
| Amphetamines | ↑ Amphetamines | Use with caution. |
| Antidepressant: trazodone | ↑ trazodone | Concomitant use of trazodone and RESCRIPTOR may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as RESCRIPTOR, the combination should be used with caution and a lower dose of trazadone should be considered. |
| Antiarrhythmics: bepridil | ↑ Antiarrhythmics | Use with caution. Increased bepridil exposure may be associated with life-threatening reactions such as cardiac arrhythmias. |
| Amiodarone, lidocaine (systemic), quinidine, flecainide, propafenone | Caution is warranted and therapeutic concentration monitoring is recommended, if available, for antiarrhythmics when coadministered with RESCRIPTOR. | |
| Anticoagulant: warfarin | ↑ Warfarin | It is recommended that INR (international normalized ratio) be monitored. |
| Anti-infective: clarithromycin | ↑ Clarithromycin | When coadministered with RESCRIPTOR, clarithromycin should be adjusted in patients with impaired renal function:
|
| Calcium channel blockers: amlodipine, diltiazem, felodipine, isradipine, nifedipine, nicardipine, nimodipine, nisoldipine, verapamil | ↑ Calcium channel blockers | Caution is warranted and clinical monitoring of patients is recommended. |
| Corticosteroid: dexamethasone | ↓ Delavirdine | Use with caution. RESCRIPTOR may be less effective due to decreased delavirdine plasma concentrations in patients taking these agents concomitantly. |
| Erectile dysfunction agents: sildenafil | ↑ Sildenafil | Sildenafil should not exceed a maximum single dose of 25 mg in a 48-hour period. |
| HMG-CoA reductase inhibitors: atorvastatin, cerivastatin, fluvastatin | ↑ Atorvastatin ↑ Cerivastatin ↑ Fluvastatin | Use lowest possible dose of atorvastatin or cerivastatin, or fluvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin in combination with RESCRIPTOR. |
| Immunosuppressants: cyclosporine, tacrolimus, rapamycin | ↑ Immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with RESCRIPTOR. |
| Inhaled/nasal steroid: Fluticasone | ↑ fluticasone | Concomitant use of fluticasone propionate and RESCRIPTOR may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use. |
| Narcotic analgesic: methadone | ↑ Methadone | Dosage of methadone may need to be decreased when coadministered with RESCRIPTOR. |
| Oral contraceptives: ethinyl estradiol | ↑ Ethinyl estradiol | Concentrations of ethinyl estradiol may increase. However, the clinical significance is unknown. |
|
Specific Drugs |
|
|
|---|---|---|
|
|
||
|
didanosine buffered formulations enteric-coated (EC) capsules |
↓ atazanavir ↓ didanosine |
Coadministration of REYATAZ with didanosine buffered tablets resulted in a marked decrease in atazanavir exposure. It is recommended that REYATAZ be given (with food) 2 h before or 1 h after didanosine buffered formulations. Simultaneous administration of didanosine EC and REYATAZ with food results in a decrease in didanosine exposure. Thus, REYATAZ and didanosine EC should be administered at different times. |
|
|
↓ atazanavir ↑ tenofovir |
Tenofovir may decrease the AUC and Cmin of atazanavir. When coadministered with tenofovir, it is recommended that REYATAZ 300 mg be given with ritonavir 100 mg and tenofovir 300 mg (all as a single daily dose with food). |
|
|
↓ atazanavir | Efavirenz decreases atazanavir exposure. If REYATAZ is combined with efavirenz, REYATAZ 400 mg (two 200-mg capsules) with ritonavir 100 mg should be administered once daily all as a single dose with food, and efavirenz 600 mg should be administered once daily on an empty stomach, preferably at bedtime. Do not coadminister REYATAZ with efavirenz in treatment-experienced patients due to decreased atazanavir exposure. |
| nevirapine | ↓ atazanavir ↑ nevirapine |
Do not coadminister REYATAZ with nevirapine because:
|
|
saquinavir (soft gelatin capsules) |
↑ saquinavir | Appropriate dosing recommendations for this combination, with or without ritonavir, with respect to efficacy and safety have not been established. In a clinical study, saquinavir 1200 mg coadministered with REYATAZ 400 mg and tenofovir 300 mg (all given once daily) plus nucleoside analogue reverse transcriptase inhibitors did not provide adequate efficacy [see |
| ritonavir | ↑ atazanavir | If REYATAZ is coadministered with ritonavir, it is recommended that REYATAZ 300 mg once daily be given with ritonavir 100 mg once daily with food. See the complete prescribing information for NORVIR® (ritonavir) for information on drug interactions with ritonavir. |
| others | ↑ other protease inhibitor |
|
|
|
||
|
boceprevir |
↓ atazanavir ↓ ritonavir |
Concomitant administration of boceprevir and atazanavir/ritonavir resulted in reduced steady-state exposures to atazanavir and ritonavir. Coadministration of REYATAZ/ritonavir and boceprevir is not recommended. |
| telaprevir | ↓ telaprevir ↑ atazanavir |
Concomitant administration of telaprevir and atazanavir/ritonavir resulted in reduced steady-state telaprevir exposure, while steady-state atazanavir exposure was increased. |
|
|
||
|
|
↓ atazanavir | Reduced plasma concentrations of atazanavir are expected if antacids, including buffered medications, are administered with REYATAZ. REYATAZ should be administered 2 hours before or 1 hour after these medications. |
|
|
↑ amiodarone, bepridil, lidocaine (systemic), quinidine | Coadministration with REYATAZ has the potential to produce serious and/or life-threatening adverse events and has not been studied. Caution is warranted and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ (atazanavir sulfate). |
|
|
↑ warfarin | Coadministration with REYATAZ has the potential to produce serious and/or life-threatening bleeding and has not been studied. It is recommended that INR (International Normalized Ratio) be monitored. |
|
|
↑ tricyclic antidepressants | Coadministration with REYATAZ has the potential to produce serious and/or life-threatening adverse events and has not been studied. Concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ. |
| trazodone | ↑ trazodone | Concomitant use of trazodone and REYATAZ with or without ritonavir may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as REYATAZ, the combination should be used with caution and a lower dose of trazodone should be considered. |
|
carbamazepine |
↓ atazanavir ↑ carbamazepine |
Plasma concentrations of atazanavir may be decreased when carbamazepine is administered with REYATAZ without ritonavir. Coadministration of carbamazepine and REYATAZ without ritonavir is not recommended. Ritonavir may increase plasma levels of carbamazepine. If patients beginning treatment with REYATAZ/ritonavir have been titrated to a stable dose of carbamazepine, a dose reduction for carbamazepine may be necessary. |
| phenytoin, phenobarbital | ↓ atazanavir ↓ phenytoin ↓ phenobarbital |
Plasma concentrations of atazanavir may be decreased when phenytoin or phenobarbital is administered with REYATAZ without ritonavir. Coadministration of phenytoin or phenobarbital and REYATAZ without ritonavir is not recommended. Ritonavir may decrease plasma levels of phenytoin and phenobarbital. When REYATAZ with ritonavir is coadministered with either phenytoin or phenobarbital, a dose adjustment of phenytoin or phenobarbital may be required. |
| lamotrigine | ↓ lamotrigine | Coadministration of lamotrigine and REYATAZ |
|
ketoconazole, itraconazole |
↑ ketoconazole ↑ itraconazole |
Coadministration of ketoconazole has only been studied with REYATAZ without ritonavir (negligible increase in atazanavir AUC and Cmax). Due to the effect of ritonavir on ketoconazole, high doses of ketoconazole and itraconazole (>200 mg/day) should be used cautiously with REYATAZ/ritonavir. |
| voriconazole |
↓ voriconazole ↓ atazanavir ↑ voriconazole ↓ atazanavir |
Voriconazole should not be administered to patients receiving REYATAZ/ritonavir, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Patients should be carefully monitored for voriconazole-associated adverse events and loss of either voriconazole or atazanavir efficacy during the co-administration of voriconazole and REYATAZ/ritonavir. Coadministration of voriconazole with REYATAZ (without ritonavir) may affect atazanavir concentrations; however, no data are available. |
|
|
↑ colchicine | REYATAZ should not be coadministered with colchicine to patients with renal or hepatic impairment. Treatment of gout flares: 0.6 mg (1 tablet) for 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Not to be repeated before 3 days. If the original regimen was 0.6 mg If the original regimen was 0.6 mg Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). |
|
|
↑ rifabutin | A rifabutin dose reduction of up to 75% (eg, 150 mg every other day or 3 times per week) is recommended. Increased monitoring for rifabutin-associated adverse reactions including neutropenia is warranted. |
|
|
↑ midazolam | Concomitant use of parenteral midazolam with REYATAZ may increase plasma concentrations of midazolam. Coadministration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Coadministration of oral midazolam with REYATAZ is CONTRAINDICATED. |
|
|
↑ diltiazem and desacetyl-diltiazem | Caution is warranted. A dose reduction of diltiazem by 50% should be considered. ECG monitoring is recommended. Coadministration of REYATAZ/ritonavir with diltiazem has not been studied. |
| felodipine, nifedipine, nicardipine, and verapamil | ↑ calcium channel blocker | Caution is warranted. Dose titration of the calcium channel blocker should be considered. ECG monitoring is recommended. |
|
|
↓ atazanavir ↑ bosentan |
Plasma concentrations of atazanavir may be decreased when bosentan is administered with REYATAZ without ritonavir. Coadministration of bosentan and REYATAZ without ritonavir is not recommended. For patients who have been receiving REYATAZ/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based on individual tolerability. Discontinue bosentan at least 36 hours before starting REYATAZ/ritonavir. At least 10 days after starting REYATAZ/ritonavir, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability. |
|
|
↑ atorvastatin ↑ rosuvastatin |
Titrate atorvastatin dose carefully and use the lowest necessary dose. Rosuvastatin dose should not exceed 10 mg/day. The risk of myopathy, including rhabdomyolysis, may be increased when HIV protease inhibitors, including REYATAZ, are used in combination with these drugs. |
|
|
↓ atazanavir | Plasma concentrations of atazanavir were substantially decreased when REYATAZ 400 mg once daily was administered simultaneously with famotidine 40 mg twice daily, which may result in loss of therapeutic effect and development of resistance. |
|
REYATAZ 300 mg with ritonavir 100 mg once daily with food should be administered simultaneously with, and/or at least 10 hours after, a dose of the H2-receptor antagonist. An H2-receptor antagonist dose comparable to famotidine 20 mg once daily up to a dose comparable to famotidine 40 mg twice daily can be used with REYATAZ 300 mg with ritonavir 100 mg in treatment-naive patients. OR For patients unable to tolerate ritonavir, REYATAZ 400 mg once daily with food should be administered at least 2 hours before and at least 10 hours after a dose of the H2-receptor antagonist. No single dose of the H2-receptor antagonist should exceed a dose comparable to famotidine 20 mg, and the total daily dose should not exceed a dose comparable to famotidine 40 mg. However, REYATAZ should not be used without ritonavir in pregnant women. |
||
|
Whenever an H2-receptor antagonist is given to a patient receiving REYATAZ with ritonavir, the H2-receptor antagonist dose should not exceed a dose comparable to famotidine 20 mg twice daily, and the REYATAZ and ritonavir doses should be administered simultaneously with, and/or at least 10 hours after, the dose of the H2-receptor antagonist.
|
||
|
|
↓ ethinyl estradiol ↑ norgestimatec ↑ ethinyl estradiol ↑ norethindroned |
Use with caution if coadministration of REYATAZ or REYATAZ/ritonavir with oral contraceptives is considered. If an oral contraceptive is administered with REYATAZ plus ritonavir, it is recommended that the oral contraceptive contain at least
35 mcg of ethinyl estradiol. If REYATAZ is administered without ritonavir, the oral contraceptive should contain no more than 30 mcg of ethinyl estradiol. Potential safety risks include substantial increases in progesterone exposure. The long-term effects of increases in concentration of the progestational agent are unknown and could increase the risk of insulin resistance, dyslipidemia, and acne. Coadministration of REYATAZ or REYATAZ/ritonavir with other hormonal contraceptives (eg, contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than norethindrone or norgestimate, or less than 25 mcg of ethinyl estradiol, has not been studied; therefore, alternative methods of contraception are recommended. |
|
|
↑ immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with REYATAZ (atazanavir sulfate). |
|
|
↑ salmeterol | Coadministration of salmeterol with REYATAZ is not recommended. Concomitant use of salmeterol and REYATAZ may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia. |
|
|
|
Concomitant use of fluticasone propionate and REYATAZ (without ritonavir) may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use. |
|
|
Concomitant use of fluticasone propionate and REYATAZ/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression, have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Coadministration of fluticasone propionate and REYATAZ/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects [see |
|
|
|
↑ clarithromycin ↓ 14-OH clarithromycin ↑ atazanavir |
Increased concentrations of clarithromycin may cause QTc prolongations; therefore, a dose reduction of clarithromycin by 50% should be considered when it is coadministered with REYATAZ. In addition, concentrations of the active metabolite 14-OH clarithromycin are significantly reduced; consider alternative therapy for indications other than infections due to |
|
|
↑ buprenorphine ↑ norbuprenorphine |
Coadministration of buprenorphine and REYATAZ with or without ritonavir increases the plasma concentration of buprenorphine and norbuprenorphine. Coadministration of REYATAZ plus ritonavir with buprenorphine warrants clinical monitoring for sedation and cognitive effects. A dose reduction of buprenorphine may be considered. Coadministration of buprenorphine and REYATAZ with ritonavir is not expected to decrease atazanavir plasma concentrations. Coadministration of buprenorphine and REYATAZ without ritonavir may decrease atazanavir plasma concentrations. REYATAZ without ritonavir should not be coadministered with buprenorphine. |
|
|
↑ sildenafil ↑ tadalafil ↑ vardenafil |
Coadministration with REYATAZ has not been studied but may result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of REVATIO® (sildenafil) for the treatment of pulmonary hypertension (PAH) is contraindicated with REYATAZ [see The following dose adjustments are recommended for the use of ADCIRCA® (tadalafil) with REYATAZ: Coadministration of ADCIRCA® in patients on REYATAZ (with or without ritonavir):
Coadministration of REYATAZ (with or without ritonavir) in patients on ADCIRCA®:
|
|
|
|
|
|
|
↓ atazanavir | Plasma concentrations of atazanavir were substantially decreased when REYATAZ 400 mg or REYATAZ 300 mg/ritonavir 100 mg once daily was administered with omeprazole 40 mg once daily, which may result in loss of therapeutic effect and development of resistance. |
|
The proton-pump inhibitor dose should not exceed a dose comparable to omeprazole 20 mg and must be taken approximately 12 hours prior to the REYATAZ 300 mg with ritonavir 100 mg dose. |
||
|
Proton-pump inhibitors should not be used in treatment-experienced patients receiving REYATAZ. |
|
|
|
| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. ( |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents |
Carefully monitor blood glucose ( |
| |
|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1) |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2) |
| Antidiabetic agents | Carefully monitor blood glucose (5.11, 7.3) |
|
|
|
|
|
Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
|
|
Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) | Do not exceed 40 mg atorvastatin daily |
| Concomitant Drug Class: Drug Name | Effect | Clinical Comment |
|---|---|---|
|
|
||
| Protease inhibitor: atazanavir |
↓atazanavir ↑ tenofovir |
Coadministration of atazanavir with ATRIPLA is not recommended. Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA. |
| Protease inhibitor: fosamprenavir calcium |
↓ amprenavir | Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and ATRIPLA with respect to safety and efficacy have not been established. Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when ATRIPLA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when ATRIPLA is administered with fosamprenavir plus ritonavir twice daily. |
| Protease inhibitor: indinavir |
↓ indinavir | The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz. |
| Protease inhibitor: lopinavir/ritonavir |
↓ lopinavir ↑ tenofovir |
Do not use once daily administration of lopinavir/ritonavir. Dose adjustment of lopinavir/ritonavir is recommended when coadministered with efavirenz. Refer to the full prescribing information for lopinavir/ritonavir for guidance on coadministration with efavirenz- or tenofovir-containing regimens, such as ATRIPLA. Patients should be monitored for tenofovir-associated adverse reactions. |
| Protease inhibitor: ritonavir |
↑ ritonavir ↑ efavirenz |
When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when ATRIPLA is used in combination with ritonavir. |
| Protease inhibitor: saquinavir |
↓ saquinavir | Appropriate doses of the combination of efavirenz and saquinavir/ritonavir with respect to safety and efficacy have not been established. |
| CCR5 co-receptor antagonist: maraviroc |
↓ maraviroc | Efavirenz decreases plasma concentrations of maraviroc. Refer to the full prescribing information for maraviroc for guidance on coadministration with ATRIPLA. |
| NRTI: didanosine |
↑ didanosine | Coadministration of ATRIPLA and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions including pancreatitis, lactic acidosis, and neuropathy. A dose reduction of didanosine is recommended when coadministered with tenofovir DF. For additional information on coadministration with tenofovir DF-containing products, please refer to the didanosine prescribing information. |
| NNRTI: Other NNRTIs |
↑ or ↓ efavirenz and/or NNRTI | Combining two NNRTIs has not been shown to be beneficial. ATRIPLA contains efavirenz and should not be coadministered with other NNRTIs. |
| Integrase strand transfer inhibitor: raltegravir |
↓ raltegravir | Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed. |
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| Protease inhibitor: boceprevir |
↓ boceprevir | Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with efavirenz, which may result in loss of therapeutic effect. The combination should be avoided. |
| Protease inhibitor: telaprevir |
↓ telaprevir ↓ efavirenz |
Concomitant administration of telaprevir and efavirenz resulted in reduced steady-state exposures to telaprevir and efavirenz. |
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| Anticoagulant: warfarin |
↑ or ↓ warfarin | Plasma concentrations and effects potentially increased or decreased by efavirenz. |
| Anticonvulsants: carbamazepine |
↓ carbamazepine ↓ efavirenz |
There are insufficient data to make a dose recommendation for ATRIPLA. Alternative anticonvulsant treatment should be used. |
| phenytoin phenobarbital |
↓ anticonvulsant ↓ efavirenz |
Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted. |
| Antidepressants: bupropion |
↓ buproprion | The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded. |
| sertraline | ↓ sertraline | Increases in sertraline dose should be guided by clinical response. |
| Antifungals: itraconazole |
↓ itraconazole ↓ hydroxy-itraconazole |
Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered. |
| ketoconazole | ↓ ketoconazole | Drug interaction trials with ATRIPLA and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole. |
| posaconazole | ↓ posaconazole | Avoid concomitant use unless the benefit outweighs the risks. |
| Anti-infective: clarithromycin |
↓ clarithromycin ↑ 14-OH metabolite |
Clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of ATRIPLA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with ATRIPLA. |
| Antimycobacterial: rifabutin |
↓ rifabutin | Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week. |
| rifampin | ↓ efavirenz | If ATRIPLA is coadministered with rifampin to patients weighing 50 kg or more, an additional 200 mg/day of efavirenz is recommended. |
| Calcium channel blockers: diltiazem |
↓ diltiazem ↓ desacetyl diltiazem ↓ N-monodes-methyl diltiazem |
Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of ATRIPLA is necessary when administered with diltiazem. |
| Others (e.g., felodipine, nicardipine, nifedipine, verapamil) |
↓ calcium channel blocker | No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker). |
| HMG-CoA reductase inhibitors: atorvastatin pravastatin simvastatin |
↓ atorvastatin ↓ pravastatin ↓ simvastatin |
Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose. |
| Hormonal contraceptives: | ||
| Oral: ethinyl estradiol/norgestimate |
↓ active metabolites of norgestimate | A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed. |
| Implant: etonogestrel |
↓ etonogestrel | A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients. |
| Immunosuppressants: cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A |
↓ immuno-suppressant | Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by efavirenz. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with ATRIPLA. |
| Narcotic analgesic: methadone |
↓ methadone | Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms. |
| *Not administered but an active metabolite of carbamazepine. | ||
| **No significant effect. | ||
| AED Coadministered |
AED Concentration |
Felbatol® Concentration |
| Phenytoin | ↑ | ↓ |
| Valproate | ↑ | ↔** |
| Carbamazepine (CBZ) *CBZ epoxide |
↓ ↑ |
↓ |
| Phenobarbital | ↑ | ↓ |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| Lopinavir plus ritonavir | Use lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) |
Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
|
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| Strong CYP3A4 Inhibitors, (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol |
Contraindicated with VYTORIN |
| Verapamil, diltiazem, dronedarone | Do not exceed 10/10 mg VYTORIN daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 10/20 mg VYTORIN daily |
| Grapefruit juice | Avoid grapefruit juice |
| Enzyme | Inhibitors | Inducers |
|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
| Drug Class | Specific Drugs |
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
| Drug Class: Drug Name | Clinical Comment |
|---|---|
| Alpha 1-adrenoreceptor antagonist: alfuzosin |
Potentially increased alfuzosin concentrations can result in hypotension. |
| Antiarrhythmics: amiodarone, quinidine |
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as cardiac arrhythmias. |
| Antimycobacterial: rifampin |
May lead to loss of virologic response and possible resistance to VIRACEPT or other coadministered antiretroviral agents. |
| Ergot Derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine |
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. |
| Herbal Products: St. John's wort (hypericum perforatum) |
May lead to loss of virologic response and possible resistance to VIRACEPT or other coadministered antiretroviral agents. |
| HMG-CoA Reductase Inhibitors: lovastatin, simvastatin |
Potential for serious reactions such as risk of myopathy including rhabdomyolysis. |
| Neuroleptic: pimozide |
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as cardiac arrhythmias. |
| PDE5 inhibitor: sildenafil (REVATIO) [for treatment of pulmonary arterial hypertension] |
A safe and effective dose has not been established when used with VIRACEPT. There is increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, prolonged erection, and syncope). |
| Proton Pump Inhibitors | Omeprazole decreases the plasma concentrations of nelfinavir. Concomitant use of proton pump inhibitors and VIRACEPT may lead to a loss of virologic response and development of resistance. |
| Sedative/Hypnotics: midazolam, triazolam |
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as prolonged or increased sedation or respiratory depression. |
| Concomitant Drug Class: Drug Name | Effect on Concentration | Clinical Comment | |
|---|---|---|---|
| HIV-Antiviral Agents | |||
| Non-nucleoside Reverse Transcriptase Inhibitors: | Appropriate doses for these combinations, with respect to safety and efficacy, have not been established. | ||
| delavirdine | ↑ nelfinavir ↓ delavirdine |
||
| nevirapine | ↓ nelfinavir (Cmin) | ||
| Nucleoside Reverse Transcriptase Inhibitor: didanosine |
It is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after VIRACEPT (given with food). |
||
| Protease Inhibitors: | Appropriate doses for these combinations, with respect to safety and efficacy, have not been established. | ||
| indinavir | ↑ nelfinavir ↑ indinavir |
||
| ritonavir | ↑ nelfinavir | ||
| saquinavir | ↑ saquinavir | ||
| Other Agents | |||
| Anti-coagulant: warfarin |
warfarin | Coadministration of warfarin and VIRACEPT may affect concentrations of warfarin. It is recommended that the INR (international normalized ratio) be monitored carefully during treatment with VIRACEPT, especially when commencing therapy. | |
| Anti-convulsants: | May decrease nelfinavir plasma concentrations. VIRACEPT may not be effective due to decreased nelfinavir plasma concentrations in patients taking these agents concomitantly. | ||
| carbamazepine phenobarbital |
↓ nelfinavir | ||
| Anti-convulsant: | Phenytoin plasma/serum concentrations should be monitored; phenytoin dose may require adjustment to compensate for altered phenytoin concentration. | ||
| phenytoin | ↓ phenytoin | ||
| Anti-depressant: trazodone | ↑ trazodone | Concomitant use of trazodone and VIRACEPT may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as VIRACEPT, the combination should be used with caution and a lower dose of trazodone should be considered. | |
| Anti-gout colchicine |
↑ colchicine | Treatment of gout flares– coadministration of colchicine in patients on VIRACEPT: coadministration of colchicine in patients on VIRACEPT: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. coadministration of colchicine in patients on VIRACEPT: Patients with renal or hepatic impairment should not be given colchicine with VIRACEPT. |
|
| Anti-Mycobacterial: | It is recommended that the dose of rifabutin be reduced to one-half the usual dose when administered with VIRACEPT; 1250 mg BID is the preferred dose of VIRACEPT when coadministered with rifabutin. | ||
| rifabutin | ↑ rifabutin ↓ nelfinavir (750 mg TID) ↔ nelfinavir (1250 mg BID) |
||
| Endothelin receptor antagonists: bosentan |
↑ bosentan |
|
|
| HMG-CoA Reductase Inhibitor: | Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with VIRACEPT. | ||
| atorvastatin | ↑ atorvastatin | ||
| rosuvastatin | ↑ rosuvastatin | ||
| Immuno-suppressants: | Plasma concentrations may be increased by VIRACEPT. | ||
| cyclosporine tacrolimus sirolimus |
↑ immuno-suppressants | ||
| Inhaled beta agonist: salmeterol |
↑ salmeterol | Concurrent administration of salmeterol with VIRACEPT is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. | |
| Inhaled/nasal steroid: Fluticasone | ↑ fluticasone | Concomitant use of fluticasone propionate and VIRACEPT may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use. | |
| Macrolide Antibiotic: azithromycin |
↑ azithromycin |
Dose adjustment of azithromycin is not recommended, but close monitoring for known side effects such as liver enzyme abnormalities and hearing impairment is warranted. | |
| Narcotic Analgesic: | Dosage of methadone may need to be increased when coadministered with VIRACEPT. | ||
| methadone | ↓ methadone | ||
| Oral Contraceptive: | Alternative or additional contraceptive measures should be used when oral contraceptives and VIRACEPT are coadministered. | ||
| ethinyl estradiol | ↓ ethinyl estradiol | ||
| PDE5 Inhibitors: sildenafil vardenafil tadalafil |
↑ PDE5 Inhibitors |
Concomitant use of PDE5 inhibitors and VIRACEPT should be undertaken with caution.
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| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone |
Do not exceed 10 mg simvastatin daily |
| Amiodarone, Amlodipine, ranolazine |
Do not exceed 20 mg simvastatin daily |
| Grapefruit juice |
Avoid grapefruit juice |
|
|
|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
| Co-administered Drug | Dosing Schedule | Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (Ratio |
Risperidone Dose Recommendation | ||
| Co-administered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6) Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
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| Amiodarone Iodide (including iodine- containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
| Interacting Agents | Prescribing Recommendations |
|---|---|
| Strong CYP3A4 inhibitors (e.g.,Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin |
| Verapamil, diltiazem |
Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine |
Do not exceed 20 mg simvastatin daily |
| Grapefruit juice |
Avoid large quantities of grapefruit juice (>1 quart daily) |
|
a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. b = Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. NE = Not Evaluated. |
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| AED Co-administered |
AED Concentration |
Topiramate Concentration |
| Phenytoin |
NC or 25% increasea
|
48% decrease |
| Carbamazepine (CBZ) |
NC |
40% decrease |
| CBZ epoxideb
|
NC |
NE |
| Valproic acid |
11% decrease |
14% decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NC at TPM doses up to 400 mg/day |
13% decrease |
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|---|---|---|
| * The interaction between SUSTIVA and the drug was evaluated in a clinical study. All other drug interactions shown are predicted. | ||
| This table is not all-inclusive. | ||
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| Protease inhibitor: Fosamprenavir calcium |
↓ amprenavir |
Fosamprenavir
(unboosted): Appropriate doses of the combinations with respect to safety
and efficacy have not been established. Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when SUSTIVA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when SUSTIVA is administered with fosamprenavir plus ritonavir twice daily. |
| Protease inhibitor: Atazanavir sulfate |
↓ atazanavir* |
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| Protease inhibitor: Indinavir |
↓ indinavir* |
The optimal dose of indinavir, when given in combination with SUSTIVA, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to SUSTIVA. When indinavir at an increased dose (1000 mg every 8 hours) was given with SUSTIVA (600 mg once daily), the indinavir AUC and Cmin were decreased on average by 33-46% and 39-57%, respectively, compared to when indinavir (800 mg every 8 hours) was given alone. |
| Protease inhibitor: Lopinavir/ritonavir |
↓ lopinavir* |
Lopinavir/ritonavir tablets should not be administered once daily in combination with SUSTIVA. In antiretroviral-naive patients, lopinavir/ritonavir tablets can be used twice daily in combination with SUSTIVA with no dose adjustment. A dose increase of lopinavir/ritonavir tablets to 600/150 mg (3 tablets) twice daily may be considered when used in combination with SUSTIVA in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). A dose increase of lopinavir/ritonavir oral solution to 533/133 mg (6.5 mL) twice daily taken with food is recommended when used in combination with SUSTIVA. |
| Protease inhibitor: Ritonavir |
↑ ritonavir* ↑ efavirenz* |
When ritonavir 500 mg q12h was coadministered with SUSTIVA 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (eg, dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when SUSTIVA is used in combination with ritonavir. |
| Protease inhibitor: Saquinavir |
↓ saquinavir* |
Should not be used as sole protease inhibitor in combination with SUSTIVA. |
| NNRTI: Other NNRTIs |
↑ or ↓ efavirenz and/or NNRTI |
Combining two NNRTIs has not been shown to be beneficial. SUSTIVA should not be coadministered with other NNRTIs. |
| CCR5 co-receptor antagonist: Maraviroc |
↓ maraviroc* |
Refer to the full prescribing information for maraviroc for guidance on coadministration with efavirenz. |
| Integrase strand transfer inhibitor: Raltegravir |
↓ raltegravir* |
SUSTIVA reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed. |
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| Protease inhibitor: Boceprevir |
↓ boceprevir* |
Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with SUSTIVA, which may result in loss of therapeutic effect. The combination should be avoided. |
| Protease inhibitor: Telaprevir |
↓ telaprevir* ↓ efavirenz* |
Concomitant administration of telaprevir and SUSTIVA resulted in reduced steady-state exposures to telaprevir and efavirenz. |
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| Anticoagulant: Warfarin |
↑ or ↓ warfarin |
Plasma concentrations and effects potentially increased or decreased by SUSTIVA. |
| Anticonvulsants: Carbamazepine |
↓ carbamazepine* ↓ efavirenz* |
There are insufficient data to make a dose recommendation for efavirenz. Alternative anticonvulsant treatment should be used. |
| Phenytoin Phenobarbital |
↓ anticonvulsant ↓ efavirenz |
Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted. |
| Antidepressants: Bupropion |
↓ bupropion* |
The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded. |
| Sertraline | ↓ sertraline* | Increases in sertraline dosage should be guided by clinical response. |
| Antifungals: Voriconazole |
↓ voriconazole* ↑ efavirenz* |
SUSTIVA and voriconazole must not be coadministered at standard doses. Efavirenz significantly decreases voriconazole plasma concentrations, and coadministration may decrease the therapeutic effectiveness of voriconazole. Also, voriconazole significantly increases efavirenz plasma concentrations, which may increase the risk of SUSTIVA-associated side effects. When voriconazole is coadministered with SUSTIVA, voriconazole maintenance dose should be increased to 400 mg every 12 hours and SUSTIVA dose should be decreased to 300 mg once daily using the capsule formulation. SUSTIVA tablets should not be broken. [See |
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Itraconazole |
↓ itraconazole* ↓ hydroxyitraconazole* |
Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered. |
| Ketoconazole | ↓ ketoconazole | Drug interaction studies with SUSTIVA and ketoconazole have not been conducted. SUSTIVA has the potential to decrease plasma concentrations of ketoconazole. |
| Posaconazole | ↓ posaconazole* | Avoid concomitant use unless the benefit outweighs the risks. |
| Anti-infective: Clarithromycin |
↓ clarithromycin* ↑ 14-OH metabolite* |
Plasma concentrations
decreased by SUSTIVA; clinical significance unknown. In uninfected volunteers,
46% developed rash while receiving SUSTIVA and clarithromycin. No dose adjustment
of SUSTIVA is recommended when given with clarithromycin. Alternatives to
clarithromycin, such as azithromycin, should be considered (see |
| Antimycobacterials: Rifabutin |
↓ rifabutin* |
Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week. |
| Rifampin | ↓ efavirenz* | If SUSTIVA is coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of SUSTIVA to 800 mg once daily is recommended. |
| Calcium channel blockers: Diltiazem |
↓ diltiazem* ↓ desacetyl diltiazem* ↓ N-monodesmethyl diltiazem* |
Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of efavirenz is necessary when administered with diltiazem. |
| Others (eg, felodipine, nicardipine, nifedipine, verapamil) |
↓ calcium channel blocker |
No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker). |
| HMG-CoA reductase
inhibitors: Atorvastatin Pravastatin Simvastatin |
↓ atorvastatin* ↓ pravastatin* ↓ simvastatin* |
Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose. |
| Hormonal contraceptives: Oral Ethinyl estradiol/ Norgestimate |
↓ active metabolites of norgestimate* |
A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed. |
| Implant Etonogestrel |
↓ etonogestrel |
A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients. |
| Immunosuppressants: Cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A |
↓ immunosuppressant |
Decreased exposure of the immunosuppressant may be expected due to CYP3A induction. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with efavirenz. |
| Narcotic analgesic: Methadone |
↓ methadone* |
Coadministration in HIV-infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms. |
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| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine, danazol | Do not exceed 10 mg simvastatin daily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Diltiazem | Do not exceed 40 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
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(25°C) |
(4°C) |
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| Concomitant Drug |
Effect on Concentration of Lamotrigine or Concomitant Drug |
Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine ↓ levonorgestrel |
Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%. |
| Carbamazepine (CBZ) and CBZ epoxide |
↓ lamotrigine ? CBZ epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase CBZ epoxide levels |
| Phenobarbital/Primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40%. |
| Valproate |
↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
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| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
| Alpha-Blocker | Simultaneous dosing of Vardenafil 5 mg and Alpha-Blocker, Placebo-Subtracted |
Dosing of Vardenafil 5 mg and Alpha-Blocker Separated by 6 Hours, Placebo-Subtracted |
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| Terazosin 5 or 10 mg daily |
Standing SBP | -3 (-6.7, 0.1) | -4 (-7.4, -0.5) |
| Supine SBP | -4 (-6.7, -0.5) | -4 (-7.1, -0.7) | |
| Tamsulosin 0.4 mg daily |
Standing SBP Supine SBP |
-6 (-9.9, -2.1) -4 (-7.0, -0.8) |
-4 (-8.3, -0.5) -5 (-7.9, -1.7) |
| Vardenafil 10 mg Placebo-subtracted |
Vardenafil 20 mg Placebo-subtracted |
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| Standing SBP | -4 (-6.8, -0.3) | -4 (-6.8, -1.4) |
| Supine SBP | -5 (-8.2, -0.8) | -4 (-6.3, -1.8) |
| AED co-administered | AED Concentration | Topiramate Concentration |
| Phenytoin | NC or 25% increase |
48% decrease |
| Carbamazaepine (CBZ) | NC | 40% decrease |
| CBZ epoxide |
NC | NE |
| Valproic acid | 11% decrease | 14% decrease |
| Phenobarbital | NC | NE |
| Primidone | NC | NE |
| Lamotrigine | NC at TPM doses up to 400mg/day | 13% decrease |
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| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine, danazol | Do not exceed 10 mg simvastatin daily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Diltiazem | Do not exceed 40 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
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| ↓ = Decreased (induces lamotrigine glucuronidation) |
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| ↑ = Increased (inhibits lamotrigine glucuronidation) |
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| ? = Conflicting data |
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| blood dyscrasias — | diarrhea | hyperthyroidism |
| see |
elevated temperature | poor nutritional state |
| cancer | hepatic disorders | steatorrhea |
| collagen vascular disease | infectious hepatitis | vitamin K deficiency |
| congestive heart failure | jaundice |
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| 5-lipoxygenase Inhibitor | Antiplatelet Drugs/Effects | Leukotriene Receptor Antagonist |
| Adrenergic Stimulants, Central | Antithyroid Drugs† | Monoamine Oxidase Inhibitors |
| Alcohol Abuse Reduction | Beta-Adrenergic Blockers | Narcotics, prolonged |
| Preparations | Cholelitholytic Agents | Nonsteroidal Anti- |
| Analgesics | Diabetes Agents, Oral | Inflammatory Agents |
| Anesthetics, Inhalation | Diuretics† | Proton Pump Inhibitors |
| Antiandrogen | Fungal Medications, | Psychostimulants |
| Antiarrhythmics† | Intravaginal, Systemic† | Pyrazolones |
| Antibiotics† | Gastric Acidity and Peptic | Salicylates |
| Aminoglycosides (oral) | Ulcer Agents† | Selective Serotonin |
| Cephalosporins, parenteral | Gastrointestinal | Reuptake Inhibitors |
| Macrolides | Prokinetic Agents | Steroids, Adrenocortical† |
| Miscellaneous | Ulcerative Colitis Agents | Steroids, Anabolic (17-Alkyl |
| Penicillins, intravenous, | Gout Treatment Agents | Testosterone Derivatives) |
| high dose | Hemorrheologic Agents | Thrombolytics |
| Quinolones (fluoroquinolones) | Hepatotoxic Drugs | Thyroid Drugs |
| Sulfonamides, long acting | Hyperglycemic Agents | Tuberculosis Agents† |
| Tetracyclines | Hypertensive Emergency Agents | Uricosuric Agents |
| Anticoagulants | Hypnotics† | Vaccines |
| Anticonvulsants† | Hypolipidemics† | Vitamins† |
| Antidepressants† | Bile Acid-Binding Resins† | |
| Antimalarial Agents | Fibric Acid Derivatives | |
| Antineoplastics† | HMG-CoA Reductase Inhibitors† | |
| Antiparasitic/Antimicrobials | ||
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| acetaminophen | fenoprofen | paroxetine |
| alcohol |
fluconazole | penicillin G, intravenous |
| allopurinol | fluorouracil | pentoxifylline |
| aminosalicylic acid | fluoxetine | phenylbutazone |
| amiodarone HCl | flutamide | phenytoin |
| argatroban | fluvastatin | piperacillin |
| aspirin | fluvoxamine | piroxicam |
| atenolol | gefitinib | pravastatin |
| atorvastatin |
gemfibrozil | prednisone |
| azithromycin | glucagon | propafenone |
| bivalirudin | halothane | propoxyphene |
| capecitabine | heparin | propranolol |
| cefamandole | ibuprofen | propylthiouracil |
| cefazolin | ifosfamide | quinidine |
| cefoperazone | indomethacin | quinine |
| cefotetan | influenza virus vaccine | rabeprazole |
| cefoxitin | itraconazole | ranitidine |
| ceftriaxone | ketoprofen | rofecoxib |
| celecoxib | ketorolac | sertraline |
| cerivastatin | lansoprazole | simvastatin |
| chenodiol | lepirudin | stanozolol |
| chloramphenicol | levamisole | streptokinase |
| chloral hydrate |
levofloxacin | sulfamethizole |
| chlorpropamide | levothyroxine | sulfamethoxazole |
| cholestyramine |
liothyronine | sulfinpyrazone |
| cimetidine | lovastatin | sulfisoxazole |
| ciprofloxacin | mefenamic acid | sulindac |
| cisapride | methimazole |
tamoxifen |
| clarithromycin | methyldopa | tetracycline |
| clofibrate | methylphenidate | thyroid |
| warfarin sodium overdose | methylsalicylate ointment (topical) | ticarcillin |
| cyclophosphamide |
metronidazole | ticlopidine |
| danazol | miconazole | tissue plasminogen |
| dextran | (intravaginal, oral, systemic) | activator (t-PA) |
| dextrothyroxine | moricizine hydrochloride |
tolbutamide |
| diazoxide | nalidixic acid | tramadol |
| diclofenac | naproxen | trimethoprim/sulfamethoxazole |
| dicumarol | neomycin | urokinase |
| diflunisal | norfloxacin | valdecoxib |
| disulfiram | ofloxacin | valproate |
| doxycycline | olsalazine | vitamin E |
| erythromycin | omeprazole | zafirlukast |
| esomeprazole | oxandrolone | zileuton |
| ethacrynic acid | oxaprozin | |
| ezetimibe | oxymetholone | |
| fenofibrate | pantoprazole | |
| edema | hypothyroidism |
| hereditary coumarin resistance | nephrotic syndrome |
| hyperlipemia |
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| Adrenal Cortical Steroid Inhibitors | Antipsychotic Medications | Hypolipidemics† |
| Antacids | Antithyroid Drugs† | Bile Acid-Binding Resins† |
| Antianxiety Agents Antiarrhythmics† |
Barbiturates Diuretics† |
HMG-CoA Reductase Inhibitors† |
| Anticonvulsants† | Enteral Nutritional Supplements | Immunosuppressives |
| Antidepressants† | Fungal Medications, Systemic† | Oral Contraceptives, |
| Antihistamines | Gastric Acidity and Peptic Ulcer Agents† | Estrogen Containing |
| Antineoplastics† | Hypnotics† | Selective Estrogen Receptor Modulators |
| Steroids, Adrenocortical† | ||
| Tuberculosis Agents†
Vitamins† |
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| alcohol |
warfarin sodium underdosage | phenytoin |
| aminoglutethimide | cyclophosphamide |
pravastatin |
| amobarbital | dicloxacillin | prednisone |
| atorvastatin |
ethchlorvynol | primidone |
| azathioprine | glutethimide | propylthiouracil |
| butabarbital | griseofulvin | raloxifene |
| butalbital | haloperidol | ranitidine |
| carbamazepine | meprobamate | rifampin |
| chloral hydrate |
6-mercaptopurine | secobarbital |
| chlordiazepoxide | methimazole |
spironolactone |
| chlorthalidone | moricizine hydrochloride |
sucralfate |
| cholestyramine |
nafcillin | trazodone |
| clozapine | paraldehyde | vitamin C (high dose) |
| corticotropin | pentobarbital | vitamin K |
| cortisone | phenobarbital | |
| albuterol, systemic and inhaled | mebendazole |
| amoxicillin | medroxyprogesterone |
| ampicillin, with or without sulbactam | methylprednisolone |
| atenolol | metronidazole |
| azithromycin | metoprolol |
| caffeine, dietary ingestion | nadolol |
| cefaclor | nifedipine |
| co-trimoxazole (trimethoprim and | nizatidine |
| sulfamethoxazole) | norfloxacin |
| diltiazem | ofloxacin |
| dirithromycin | omeprazole |
| enflurane prednisone, | prednisolone |
| famotidine | ranitidine |
| felodipine | rifabutin |
| finasteride | roxithromycin |
| hydrocortisone | sorbitol (purgative doses do not inhibit |
| isoflurane | theophylline absorption) |
| isoniazid | sucralfate |
| isradipine | terbutaline, systemic |
| influenza vaccine | terfenadine |
| ketoconazole | tetracycline |
| lomefloxacin | tocainide |
| Concomitant Drug |
Effect on Concentration of Lamotrigine or Concomitant Drug |
Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine ↓ levonorgestrel |
Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%. |
| Carbamazepine (CBZ) and CBZ epoxide |
↓ lamotrigine ? CBZ epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase CBZ epoxide levels |
| Phenobarbital/Primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40%. |
| Valproate |
↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
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| AED Co-administered |
AED Concentration |
Topiramate Concentration |
| Phenytoin |
NC or 25% increasea
|
48% decrease |
| Carbamazepine (CBZ) |
NC |
40% decrease |
| CBZ epoxideb
|
NC |
NE |
| Valproic acid |
11% decrease |
14% decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NC at TPM doses up to 400 mg/day |
13% decrease |
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| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine | Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide | ↓ lamotrigine | Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels. | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine | Increased lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. | |
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| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
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| Phenytoin | NC or 25% increasea | 48% decrease |
| Carbamazepine (CBZ) | NC | 40% decrease |
| CBZ epoxideb | NC | NE |
| Valproic acid | 11% decrease | 14% decrease |
| Phenobarbital | NC | NE |
| Primidone | NC | NE |
| Lamotrigine | NC at TPM doses up to 400 mg/day | 13% decrease |
| Drug | Type of Interaction | Effect† |
| Adenosine | Theophylline blocks adenosine receptors. | Higher doses of adenosine may berequired to achieve desired effect. |
| Alcohol | A single large dose of alcohol (3 mL/kg ofwhiskey) decreases theophylline clearance for up to24 hours | 30% increase |
| Allopurinol | Decreases theophylline clearance at allopurinoldoses 600 mg/day | 25% increase |
| Aminoglutethimide | Increases theophylline clearance by induction ofmicrosomal enzyme activity. | 25% decrease |
| Carbamazepine | Similar to aminoglutethimide. | 30% decrease |
| Cimetidine | Decreases theophylline clearance by inhibitingcytochrome P450 1A2 | 70% increase |
| Ciprofloxacin | Similar to cimetidine. | 40% increase |
| Clarithromycin | Similar to erythromycin. | 25% increase |
| Diazepam | Benzodiazepines increase CNS concentratrionsof adenosine, a potent CNS depressant, whiletheophylline blocks adenosine receptors. | Larger diazepam doses may be requiredto produce desired level of sedation.Discontinuation of theophylline withoutreduction of diazepam dose may resultin respiratory depression. |
| Disulfiram | Decreases theophylline clearance by inhibitinghydroxylation and demethylation. | 50% increase |
| Enoxacin | Similar to cimetidine. | 300% increase |
| Ephedrine | Synergistic CNS effects | Increased frequency of nausea,nervousness, and insomnia. |
| Erythromycin | Erythromycin metabolite decreases theophyllineclearance by inhibiting cytochrome P450 3A3. | 35% increase. Erythromycin steady-state serum concentrations decrease by asimilar amount. |
| Estrogen | Estrogen containing oral contraceptives decreasetheophylline clearance in a dose-dependentfashion. The effect of progesterone on theophyllineclearance in unknown. | 30% increase |
| Flurazepam | Similar to diazepam. | Similar to diazepam. |
| Fluvoxamine | Similar to cimetidine. | Similar to cimetidine. |
| Halothane | Halothane sensitizes the myocardium tocatecholamines, theophylline increases release ofendogenous catecholamines. | Increased risk of ventriculararrhythmias. |
| Interferon, human recombinant alpha-A | Decreases theophylline clearance. | 100% increase |
| Isoproterenol (IV) | Increase theophylline clearance. | 20% increase |
| Ketamine | Pharmacologic | May lower theophylline seizurethreshold. |
| Lithium | Theophylline increases renal lithium clearance. | Lithium dose required to achievea therapeutic serum concentrationincreased an average of 60%. |
| Lorazepam | Similar to diazepam. | Similar to diazepam. |
| Methotrexate (MTX) | Decreases theophylline clearance. | 20% increase after low dose MTX,higher dose MTX may have a greatereffect. |
| Mexiletine | Similar to disulfiram. | 80% increase |
| Midazolam | Similar to diazepam. | Similar to diazepam. |
| Moricizine | Increases theophylline clearance. | 25% increase |
| Pancuronium | Theophylline may antagonize non-depolarizingneuromuscular blocking effects;possibly due tophosphodiesterase inhibition. | Larger dose of pancuronium may berequired to achieve neuromuscularblockade. |
| Pentoxifylline | Decreases theophylline clearance. | 30% increase |
| Phenobarbital (PB) | Similar to aminoglutethimide. | 25% decrease after two weeks ofconcurrent PB. |
| Phenytoin | Phenytoin increases theophylline clearance byincreasing microsomal enzyme activity. | Serum theophylline and phenytoinconcentrations decrease about 40%. |
| Propafenone | Decreases theophylline clearance andpharmacologic interaction. | 40% increase. Beta-2 blocking effectmay decrease efficacy of theophylline. |
| Propranolol | Similar to cimetidine and pharmacologicinteraction. | 100% increase Beta-2 blocking effectmay decrease efficacy of theophylline |
| Rifampin | Increases theophylline clearance by increasingcytochrome P450 1A2 and 3A3 activity. | 20-40% decrease |
| Sulfinpyrazone | Increase theophylline clearance by increasingdemethylation and hydroxylation. Decreases renalclearance of theophylline. | 20% increase |
| Tacrine | Similar to cimetidine, also increases renalclearance of theophylline. | 90% increase |
| Thiabendazole | Decreases theophylline clearance. | 190% increase |
| Ticlopidine | Decreases theophylline clearance. | 60% increase |
| Troleandomycin | Similar to erythromycin. | 33-100% increase depending ontroleandomycin dose. |
| Verapamil | Similar to disulfiram. | 20% increase |
| albuterol, | famotidine | nizatidine |
| systemic and inhaled | felodipine | norfloxacin |
| amoxicillin | finasteride | ofloxacin |
| ampicillin, | hydrocortisone | omeprazole |
| with or without | isoflurane | prednisone, prednisolone |
| sulbactam | isoniazid | ranitidine |
| atenolol | isradipine | rifabutin |
| azithromycin | influenza vaccine | roxithromycin |
| caffeine, | ketoconazole | sorbitol |
| dietary digestion | lomefloxacin | (purgative doses do not |
| cefaclor | mebendazole | inhibit theophylline |
| co-trimoxazole | medroxyprogesterone | absorption) |
| (trimethoprim and | methylprednisolone | sucralfate |
| sulfamethoxazole) | metronidazole | terbutaline, systemic |
| diltiazem | metoprolol | terfenadine |
| dirithromycin | nadolol | tetracycline |
| enflurane | nifedipine | tocainide |
|
ciprofloxacin gentamicin tobramycin trimethoprim with sulfamethoxazole vancomycin |
melphalan amphotericin B ketoconazole |
azapropazon colchicine diclofenac naproxen sulindac |
cimetidine ranitidine tacrolimus fibric acid derivatives (e.g., bezafibrate, fenofibrate) |
|
|
|
|
|
|
| diltiazem | fluconazole | azithromycin | methylprednisolone | allopurinol |
| nicardipine | itraconazole | clarithromycin | amiodarone | |
| verapamil | ketoconazole | erythromycin | bromocriptine | |
| voriconazole | quinupristin/dalfopristin | colchicine | ||
| danazol | ||||
| imatinib | ||||
| metoclopramide | ||||
| nefazodone | ||||
| oral contraceptives |
|
|
|
|
|
| nafcillin | carbamazepine | bosentan | terbinafine |
| rifampin | oxcarbazepine | octreotide | ticlopidine |
| phenobarbital | orlistat | St. John's Wort | |
| phenytoin | sulfinpyrazone | ||
|
|
|
| Antacids, sucralfate, multivitamins, and other products containing multivalent cations | Moxifloxacin absorption is decreased. Administer AVELOX Tablet at least 4 hours before or 8 hours after these products. ( |
| Warfarin | Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. ( |
| Class IA and Class III antiarrhythmics: | Proarrhythmic effect may be enhanced. Avoid concomitant use. ( |
|
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||
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|
|||
| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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|
|
|||
| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
|
|
|||
|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
| |
|||
|
|
|
||
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
||
|
|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
| |
|||
| |
|||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
|
|
|||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
|
|
|||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
|
|
|
| Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol |
Contraindicated with VYTORIN |
| Verapamil, diltiazem | Do not exceed 10/10 mg VYTORIN daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 10/20 mg VYTORIN daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of this product. |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding |
| Antidiabetic agents | Carefully monitor blood glucose |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
|---|---|---|
| ↓= Decreased (induces lamotrigine glucuronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ? = Conflicting data. |
||
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine | Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide | ↓ lamotrigine | Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels. | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine | Increased lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. | |
|
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||
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|
|||
| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
|
|
|||
|
|
|||
| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone Iodide (including iodine- containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
|
|
|||
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
|
|
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|
|
|
||
|
|
|
||
| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
|
|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
|
|
|||
|
|
|||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
|
|
|||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
|
|
|||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
| Alpha-Blocker | Simultaneous dosing of Vardenafil 5 mg and Alpha-Blocker, Placebo-Subtracted |
Dosing of Vardenafil 5 mg and Alpha-Blocker Separated by 6 Hours, Placebo-Subtracted |
|
| Terazosin 5 or 10 mg daily |
Standing SBP | -3 (-6.7, 0.1) | -4 (-7.4, -0.5) |
| Supine SBP | -4 (-6.7, -0.5) | -4 (-7.1, -0.7) | |
| Tamsulosin 0.4 mg daily |
Standing SBP Supine SBP |
-6 (-9.9, -2.1) -4 (-7.0, -0.8) |
-4 (-8.3, -0.5) -5 (-7.9, -1.7) |
| Vardenafil 10 mg Placebo-subtracted |
Vardenafil 20 mg Placebo-subtracted |
|
| Standing SBP | -4 (-6.8, -0.3) | -4 (-6.8, -1.4) |
| Supine SBP | -5 (-8.2, -0.8) | -4 (-6.3, -1.8) |
|
|
|
|
|
|
|
|
|
|
Dopamine / Dopamine Agonists
Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day). |
|
|
|
|
|
|
|
Aminoglutethimide
Amiodarone Iodide(including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
|
|
|
|
Amiodarone Iodide(including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
|
|
|
|
Antacids - Aluminum and Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
|
|
|
|
|
|
|
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
|
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4, and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
|
|
|
|
|
|
|
Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
|
|
|
|
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of
T4 to T3, leading to decreased
T3 levels. However, serum T4
levels are usually normal but may occasionally be slightly increased. In
patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change
slightly, TSH levels remain normal, and patients are clinically euthyroid. It
should be noted that actions of particular beta-adrenergic antagonists may be
impaired when the hypothyroid patient is converted to the euthyroid state.
Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may
result in slightly decreased T3 and T4
levels due to decreased TBG production (see
|
|
|
|
|
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
|
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
|
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
|
Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
|
Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
|
Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
|
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms. |
|
Dopamine / Dopamine Agonists
Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day). |
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|
Aminoglutethimide
Amiodarone Iodide(including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
|
|
|
|
Amiodarone Iodide(including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
|
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|
Antacids - Aluminum and Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
|
|
|
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|
|
|
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
|
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4, and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
|
|
|
|
|
|
|
Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
|
|
|
|
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of
T4 to T3, leading to decreased
T3 levels. However, serum T4
levels are usually normal but may occasionally be slightly increased. In
patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change
slightly, TSH levels remain normal, and patients are clinically euthyroid. It
should be noted that actions of particular beta-adrenergic antagonists may be
impaired when the hypothyroid patient is converted to the euthyroid state.
Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may
result in slightly decreased T3 and T4
levels due to decreased TBG production (see
|
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|
|
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
|
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
|
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
|
Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
|
Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
|
Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
|
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms. |
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
| Coadministered Drugs | Effect on Rifabutin | Effect on Coadministered Drug | Comments |
|---|---|---|---|
| ANTIVIRALS | |||
| Amprenavir | 2.9-fold ↑ AUC, 2.2-fold ↑ Cmax | No significant change in kinetics. | A 50% reduction in the rifabutin dose is recommended when combined with amprenavir. Increased monitoring for adverse reactions is warranted. |
| Delavirdine | ND | Oral clearance ↑ 5-fold resulting in significantly lower mean trough plasma concentrations (18±15 to 1.0±0.7 µM) | Study conducted in HIV-1 infected patients Rifabutin is not recommended for patients dosed with delavirdine mesylate 400 mg q8h. |
| Didanosine | No significant change in kinetics. | No significant change in kinetics at steady state. | |
| Fosamprenavir/ritonavir | 64% ↑ AUC |
35% ↑ AUC and 36% ↑ Cmax, no effect Ctrough (amprenavir) | Dosage reduction of rifabutin by at least 75% (to 150 mg every other day or three times per week) is recommended when combined with fosamprenavir |
| Indinavir | 204% ↑ in AUC | 32%↓ in AUC | |
| Lopinavir/ritonavir | 5.7-fold ↑ AUC, 3.4 fold ↑ Cmax |
No significant change in lopinavir kinetics. | Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted. Further dosage reduction of rifabutin may be necessary. |
| Saquinavir | ND | 40% ↓ in AUC | |
| Ritonavir | 4 fold increase in AUC, 2.5 fold increase in Cmax | ND | In the presence of ritonavir the subsequent risk of side effects, including uveitis may be increased . If a protease inhibitor is required in a patient treated with rifabutin, agents other than ritonavir should be considered. |
| Tipranavir/ritonavir[133] | 2.9-fold ↑ AUC, 1.7-fold ↑ Cmax | No significant change in tipranavir kinetics. | Therapeutic drug monitoring of rifabutin is recommended. |
| Zidovudine | No significant change in kinetics. | Approximately 32%↓ in Cmax and AUC | A large controlled clinical study has shown that these changes are of no clinical relevance. |
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| ANTIFUNGALS | 82% ↑ in AUC | No significant change in steady-state plasma concentrations | |
| Itraconazole | ND | 70% to 75% ↓ in Cmax and AUC | One case report suggests a kinetic interaction resulting in an increase in serum rifabutin levels and a risk for developing uveitis in the presence of itraconazole. |
| Posaconazole | 31%↑ Cmax, 72%↑ AUC | 43%↓ Cmax, 49%↓ AUC | If the drugs are co-administered, patients should be monitored for adverse events associated with rifabutin administration. |
| Voriconazole | 195%↑ Cmax, 331%↑ AUC |
Rifabutin (300 mg once daily) decreased the Cmax and AUC of voriconazole at 200 mg twice daily by 69% and 78%, respectively. During co-administration with rifabutin, the Cmax and AUC of voriconazole at 350 mg twice daily were 96% and 68% of the levels when administered alone at 200 mg twice daily. At a voriconazole dose of 400 mg twice daily Cmax and AUC were 104% and 87% higher, respectively, compared with voriconazole alone at 200 mg twice daily. | If the benefit outweighs the risk, rifabutin may be coadministered with voriconazole if the maintenance dose of voriconazole is increased to 5 mg/kg intravenously every 12 hours or from 200 mg to 350 mg orally, every 12 hours (100 mg to 200 mg orally, every 12 hours in patients less than 40 kg). Careful monitoring of full blood counts and adverse events to rifabutin (e.g. uveitis) is recommended when rifabutin is coadministered with voriconazole |
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| Dapsone | ND | Approximately 27% to 40% ↓ in AUC | Study conducted in HIV infected patients (rapid and slow acetylators). |
| Sulfamethoxazole-Trimethoprim | No significant change in Cmax and AUC | Approximately 15% to 20% ↓ in AUC | In another study, only trimethoprim (not sulfamethoxazole) had 14% ↓ in AUC and 6%↓ in Cmax but were not considered clinically significant. |
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| Azithromycin | No PK interaction | No PK interaction | |
| Clarithromycin | Approximately 77% ↑ in AUC | Approximately 50%↓ in AUC | Study conducted in HIV infected patients. Dose of rifabutin should be adjusted in the presence of clarithromycin |
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| Ethambutol | ND | No significant change in AUC or Cmax | |
| Isoniazid | ND | Pharmacokinetics not affected | |
| Pyrazinamide | ND | ND | Study data being evaluated. |
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| Methadone | ND | No significant effect | No apparent effect of rifabutin on either peak levels of methadone or systemic exposure based upon AUC. Rifabutin kinetics not evaluated. |
| Ethinylestradiol | ND | 35%↓ AUC 20%↓ Cmax |
Patients should be advised to use other methods of contraception. |
| Norethindrone | ND | 46%↓ AUC | Patients should be advised to use other methods of contraception. |
| Tacrolimus | ND | ND | Authors report that rifabutin decreases tacrolimus trough blood levels. |
| Theophylline | ND | No significant change in AUC or Cmax compared with baseline. | |
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| albuterol, systemic and inhaled | lomefloxacin mebendazole |
| amoxicillin | medroxyprogesterone |
| ampicillin, with or without sulbactam | methylprednisolone metronidazole |
| atenolol | metoprolol |
| azithromycin | nadolol |
| caffeine, dietary ingestion | nifedipine nizatidine |
| cefaclor | norfloxacin |
| co-trimoxazole (trimethoprim and sulfamethoxazole) |
ofloxacin omeprazole prednisone, prednisolone |
| diltiazem | ranitidine |
| dirithromycin | rifabutin |
| enflurane | roxithromycin |
| famotidine | sorbitol (purgative doses do not inhibit theophylline absorption) |
| felodipine | |
| finasteride | |
| hydrocortisone | |
| insoflurane | sucralfate |
| isoniazid | terbutaline, systemic |
| isradipine | terfenadine |
| influenza vaccine | tetracycline |
| ketoconazole | tocainide |
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| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine, danazol | Do not exceed 10 mg simvastatin daily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Diltiazem | Do not exceed 40 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
|
Decreased Lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide |
|
Addition of carbamazepine decreases Lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels. | |
| Phenobarbital/Primidone | ↓ Lamotrigine | Decreased Lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ Lamotrigine | Decreased Lamotrigine concentration approximately 40%. |
| Rifampin | ↓ Lamotrigine | Decreased Lamotrigine AUC approximately 40%. |
| Valproate |
|
Increased Lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
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|
|||
| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
| |
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||
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
||
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|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
| |
|||
| |
|||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
|
|
|||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
|
|
|||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
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|
|||
| Digoxin Serum Concentration Increase |
Digoxin AUC Increase |
|
|
| Quinidine | NA |
|
Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring. |
| Ritonavir | NA | 86% | |
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|
|||
| Amiodarone | 17% | 40% | Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring. |
| Propafenone | 28% | 29% | |
| Quinine | NA | 34-38% | |
| Spironolactone | NA | 44% | |
| Verapamil | NA | 24% | |
|
|
|||
| Please refer to section 12 for a complete list of drugs that were studied but reported no significant changes on digoxin exposure. |
No additional actions are required. | ||
| Drugs that Affect Renal Function |
A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDs], COX-2 inhibitors may impair the excretion of digoxin. |
|
| Antiarrthymics | Dofetilide | Concomitant administration with digoxin was associated with a higher rate of torsades de pointes. |
| Sotalol | Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin. | |
| Dronedarone | Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin. | |
| Parathyroid Hormone Analog |
Teriparatide | Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium. |
| Thyroid supplement | Thyroid | Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin. |
| Sympathomimetics | Epinephrine Norepinephrine Dopamine | Can increase the risk of cardiac arrhythmias. |
| Neuromuscular Blocking Agents |
Succinylcholine | May cause sudden extrusion of potassium from muscle cells, causing arrhythmias in patients taking digoxin. |
| Supplements | Calcium | If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients. |
| Beta-adrenergic blockers and calcium channel blockers |
Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block. | |
|
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|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
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| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
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| Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz*, nevirapine* |
↓ lopinavir | KALETRA dose increase is recommended in all patients Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz. KALETRA should not be administered once daily in combination with efavirenz or nevirapine |
| Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine |
↑ lopinavir | Appropriate doses of the combination with respect to safety and efficacy have not been established. |
| Nucleoside Reverse Transcriptase Inhibitor: didanosine |
KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food). |
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| Nucleoside Reverse Transcriptase Inhibitor: tenofovir |
↑ tenofovir | KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir. |
| Nucleoside Reverse Transcriptase Inhibitor: abacavir zidovudine |
↓ abacavir ↓ zidovudine |
KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown. |
| HIV-1 Protease Inhibitor: amprenavir* |
↑ amprenavir ↓ lopinavir |
KALETRA should not be administered once daily in combination with amprenavir |
| HIV-1 Protease Inhibitor: fosamprenavir/ritonavir |
↓ amprenavir ↓ lopinavir |
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor: indinavir* |
↑ indinavir | Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily |
| HIV-1 Protease Inhibitor: nelfinavir* |
↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir |
KALETRA should not be administered once daily in combination with nelfinavir |
| HIV-1 Protease Inhibitor: ritonavir* |
↑ lopinavir | Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor: saquinavir* |
↑ saquinavir | The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir. |
| HIV-1 Protease Inhibitor: tipranavir |
↓ lopinavir AUC and Cmin | KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily). |
| HIV CCR5 – Antagonist: maraviroc |
↑ maraviroc | Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry® (maraviroc). |
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| Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), quinidine |
↑ antiarrhythmics | Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA. |
| Anticancer Agents: vincristine, vinblastine, dasatinib, nilotinib |
↑ anticancer agents | Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents. For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions. |
| Anticoagulant: warfarin |
Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored. | |
| Anticonvulsants: carbamazepine, phenobarbital, phenytoin |
↓ lopinavir ↓ phenytoin |
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA. |
| Antidepressant: bupropion |
↓ bupropion ↓ active metabolite, hydroxybupropion |
Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion. |
| Antidepressant: trazodone |
↑ trazodone | Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered. |
| Anti-infective: clarithromycin |
↑ clarithromycin | For patients with renal impairment, the following dosage adjustments should be considered: • For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. • For patients with CLCR < 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary. |
| Antifungals: ketoconazole*, itraconazole, voriconazole |
↑ ketoconazole ↑ itraconazole ↓ voriconazole |
High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended. Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients. |
| Anti-gout: colchicine |
↑ colchicine | Patients with renal or hepatic impairment should not be given colchicine with KALETRA. 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). |
| Antimycobacterial: rifabutin* |
↑ rifabutin and rifabutin metabolite | Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary. |
| Antimycobacterial: rifampin |
↓ lopinavir | May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone |
| Antiparasitic: atovaquone |
↓ atovaquone | Clinical significance is unknown; however, increase in atovaquone doses may be needed. |
| Benzodiazepines: parenterally administered midazolam | ↑ midazolam | Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam |
| Calcium Channel Blockers: dihydropyridine, felodipine, nifedipine, nicardipine |
↑ dihydropyridine calcium channel blockers | Caution is warranted and clinical monitoring of patients is recommended. |
| Contraceptive: ethinyl estradiol* |
↓ ethinyl estradiol | Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended. |
| Corticosteroid: dexamethasone |
↓ lopinavir | Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly. |
| disulfiram/metronidazole | KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole). | |
| Endothelin Receptor Antagonists: bosentan |
↑ bosentan |
In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. |
| HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin |
↑ atorvastatin ↑ rosuvastatin |
Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day. See Drugs with No Observed or Predicted Interactions with KALETRA |
| Immunosuppressants: cyclosporine, tacrolimus, rapamycin |
↑ immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA. |
| Inhaled Steroid: fluticasone |
↑ fluticasone | Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect. |
| Long-acting beta-adrenoceptor Agonist: salmeterol |
↑ salmeterol | Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
| Narcotic Analgesic: methadone* fentanyl |
↓ methadone ↑ fentanyl |
Dosage of methadone may need to be increased when co-administered with KALETRA. Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA. |
| PDE5 inhibitors: sildenafil, tadalafil, vardenafil |
↑ sildenafil ↑ tadalafil ↑ vardenafil |
Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA The following dose adjustments are recommended for use of tadalafil (Adcirca®) with KALETRA: In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: It is recommended not to exceed the following doses: • Sildenafil: 25 mg every 48 hours • Tadalafil: 10 mg every 72 hours • Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events. |
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| CYP2C9 |
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast |
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 |
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton |
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 |
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton |
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
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| Anticoagulants |
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents |
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents |
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors |
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
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| No fentanyl | 6.4 ± 0.0 | 6.3 ± 0.4 |
| 3 µg/kg fentanyl | 3.5 ± 1.9 (46%) | 3.1 ± 0.6 (51%) |
| 6 µg/kg fentanyl | 3.0 ± 1.2 (53%) | 2.3 ± 1.0 (64%) |
| No midazolam | 6.9 ± 0.1 | 5.9 ± 0.6 |
| 25 µg/kg midazolam | - | 4.9 ± 0.9 (16%) |
| 50 µg/kg midazolam | - | 4.9 ± 0.5 (17%) |
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| 0.65 MAC 60% N2O/O2 | 26 | 123 | - | - |
| 1.25 MAC 60% N2O/O2 | 18 | 91 | - | - |
| 1.25 MAC O2 | 22 | 120 | 362 | 19 |
| Co-administered Drug | Dosing Schedule | Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (Ratio |
Risperidone Dose Recommendation | ||
| Co-administered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6) Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
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(Peak plasma concentration) |
(Extent of systemic exposure) |
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| Erythromycin (500 mg every 8 hrs) |
+82% | +109% |
| Ketoconazole (400 mg once daily) |
+135% | +164% |
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) | Do not exceed 40 mg atorvastatin daily |
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Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
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Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
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Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function. |
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Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4 . Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
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Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
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Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
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- Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
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- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
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- Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
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- Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
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- Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
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- (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
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Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
| Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) | VIAGRA 25 mg |
|---|---|
| Supine | 7.4 (-0.9, 15.7) |
| Standing | 6.0 (-0.8, 12.8) |
|
|
|
|
|
|
|
|
| Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) | VIAGRA 100 mg |
|---|---|
| Supine | 7.9 (4.6, 11.1) |
| Standing |
4.3 (-1.8,10.3) |
|
|
|
|
|
|
|
||
|
|
|||
| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
|
|
|||
|
|
|||
| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone Iodide (including iodine- containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
|
|
|||
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
|
|
|||
|
|
|
||
|
|
|
||
| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
|
|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
|
|
|||
|
|
|||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
|
|
|||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
|
|
|||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
| Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) | VIAGRA 25 mg |
|---|---|
| Supine | 7.4 (-0.9, 15.7) |
| Standing | 6.0 (-0.8, 12.8) |
|
|
|
|
|
|
|
|
| Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) | VIAGRA 100 mg |
|---|---|
| Supine | 7.9 (4.6, 11.1) |
| Standing |
4.3 (-1.8,10.3) |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
| CYP2C9 |
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast |
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 |
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton |
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 |
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton |
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
|
|
|
| Anticoagulants |
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents |
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents |
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors |
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine ↓ levonorgestrel |
Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%. |
| Carbamazepine (CBZ) and CBZ epoxide | ↓ lamotrigine ? CBZ epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase CBZ epoxide levels |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
| AED Coadministered | AED Concentration | Topiramate Concentration |
| Phenytoin | NC or 25% increase |
48% decrease |
| Carbamazepine (CBZ) | NC | 40% decrease |
| CBZ epoxide |
NC | NE |
| Valproic acid | 11% decrease | 14% decrease |
| Phenobarbital | NC | NE |
| Primidone | NC | NE |
| Lamotrigine | NC at TPM doses up to 400 mg/day | 13% decrease |
| NC = Less than 10% change in plasma concentration. NE = Not Evaluated. |
||
| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1) |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2) |
| Antidiabetic agents | Carefully monitor blood glucose (5.11, 7.3) |
|
|
(mg/day) |
(mg/day) |
(Mean Change, 90% Confidence Interval) |
AED on MHD Concentration (Mean Change, 90% Confidence Interval) |
| Carbamazepine | 400 to 2000 | 900 | nc1 | 40% decrease [CI: 17% decrease, 57% decrease] |
| Phenobarbital | 100 to 150 | 600 to 1800 | 14% increase [CI: 2% increase, 24% increase] |
25% decrease [CI: 12% decrease, 51% decrease] |
| Phenytoin | 250 to 500 | 600 to 1800 >1200 to 2400 |
nc1,2
up to 40% increase3 [CI: 12% increase, 60% increase] |
30% decrease [CI: 3% decrease, 48% decrease] |
| Valproic acid | 400 to 2800 | 600 to 1800 | nc1 | 18% decrease [CI: 13% decrease, 40% decrease] |
|
|
|
|
| fosaprepitant 150 mg on Day 1 | oral 2 mg on Days 1 and 4 | AUC ↑ 1.8-fold on Day 1 and AUC ↔ on Day 4 |
| fosaprepitant 100 mg on Day 1 | oral 2 mg | oral midazolam AUC ↑ 1.6-fold |
| oral aprepitant 125 mg on Day 1 and 80 mg on Days 2 to 5 | oral 2 mg SD on Days 1 and 5 | oral midazolam AUC ↑ 2.3-fold on Day 1 and ↑ 3.3-fold on Day 5 |
| oral aprepitant 125 mg on Day 1 and 80 mg on Days 2 and 3 | intravenous 2 mg prior to 3-day regimen of aprepitant and on Days 4, 8 and 15 | intravenous midazolam AUC ↑ 25% on Day 4, AUC ↓ 19% on Day 8 and AUC ↓ 4% on Day 15 |
| oral aprepitant 125 mg | intravenous 2 mg given 1 hour after aprepitant | intravenous midazolam AUC ↑ 1.5-fold |
|
|
|
|
|
|
| Carbamazepine | 400 to 2000 | 900 | nc |
40% decrease [CI: 17% decrease, 57% decrease] |
| Phenobarbital | 100 to 150 | 600 to 1800 | 14% increase [CI: 2% increase, 24% increase] | 25% decrease [CI: 12% decrease, 51% decrease] |
| Phenytoin | 250 to 500 | 600 to 1800 >1200 to 2400 | nc |
30% decrease [CI: 3% decrease, 48% decease] |
| Valproic acid | 400 to 2800 | 600 to 1800 | nc |
18% decrease [CI: 13% decrease, 40% decrease] |
|
|
|
||
|
|
|||
| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
|
|
|||
|
|
|||
| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone Iodide (including iodine- containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
|
|
|||
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
|
|
|||
|
|
|
||
|
|
|
||
| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
|
|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
|
|
|||
|
|
|||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
|
|
|||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
|
|
|||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
|
|
|
|
| Atazanavir/Ritonavir | ↓ Atazanavir ↑ Nevirapine |
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure. |
| Clarithromycin | ↓ Clarithromycin ↑ 14-OH clarithromycin |
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against |
| Efavirenz | ↓ Efavirenz | There has been no determination of appropriate doses for the safe and effective use of this combination [ |
| Ethinyl estradiol and Norethindrone | ↓ Ethinyl estradiol ↓ Norethindrone |
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended. |
| Fluconazole | ↑Nevirapine | Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events. |
| Fosamprenavir | ↓ Amprenavir ↑ Nevirapine |
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. |
| Fosamprenavir/Ritonavir | ↓ Amprenavir ↑ Nevirapine |
No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. |
| Indinavir | ↓ Indinavir | Appropriate doses for this combination are not established, but an increase in the dosage of indinavir may be required. |
| Ketoconazole | ↓ Ketoconazole | Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. |
| Lopinavir/Ritonavir | ↓Lopinavir | Lopinavir/ritonavir 400/100 mg tablets can be used twice daily in combination with nevirapine with no dose adjustment in antiretroviral-naïve patients. A dose increase of lopinavir/ritonavir tablets to 600/150 mg (3 tablets) twice daily may be considered when used in combination with nevirapine in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). A dose increase of lopinavir/ritonavir oral solution to 533/133 mg twice daily with food is recommended in combination with nevirapine. In children 6 months to 12 years of age, consideration should be given to increasing the dose of lopinavir/ritonavir to 13/3.25 mg/kg for those 7 to <15 kg; 11/2.75 mg/kg for those 15 to 45 kg; and up to a maximum dose of 533/133 mg for those >45 kg twice daily when used in combination with nevirapine, particularly for patients in whom reduced susceptibility to lopinavir/ritonavir is suspected. |
| Methadone | ↓ Methadone | Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. |
| Nelfinavir | ↓Nelfinavir M8 Metabolite ↓Nelfinavir Cmin |
The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established. |
| Rifabutin | ↑Rifabutin | Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. |
| Rifampin | ↓ Nevirapine | Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead. |
| Saquinavir/ritonavir | The interaction between VIRAMUNE and saquinavir/ritonavir has not been evaluated | The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established. |
|
|
||
|
|
|
|
| Antiarrhythmics | Amiodarone, disopyramide, lidocaine | Plasma concentrations may be decreased. |
| Anticonvulsants | Carbamazepine, clonazepam, ethosuximide | Plasma concentrations may be decreased. |
| Antifungals | Itraconazole | Plasma concentrations of some azole antifungals may be decreased. Nevirapine and itraconazole should not be administered concomitantly due to a potential decrease in itraconazole plasma concentrations. |
| Calcium channel blockers | Diltiazem, nifedipine, verapamil | Plasma concentrations may be decreased. |
| Cancer chemotherapy | Cyclophosphamide | Plasma concentrations may be decreased. |
| Ergot alkaloids | Ergotamine | Plasma concentrations may be decreased. |
| Immunosuppressants | Cyclosporin, tacrolimus, sirolimus | Plasma concentrations may be decreased. |
| Motility agents | Cisapride | Plasma concentrations may be decreased. |
| Opiate agonists | Fentanyl | Plasma concentrations may be decreased. |
| Antithrombotics | Warfarin | Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended. |
| Interacting Agents | Prescribing Recommendations |
|---|---|
| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone |
Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine |
Do not exceed 20 mg simvastatin daily |
| Grapefruit juice |
Avoid grapefruit juice |
| albuterol, | famotidine | nizatidine |
| systemic and inhaled | felodipine | norfloxacin |
| amoxicillin | finasteride | ofloxacin |
| ampicillin, | hydrocortisone | omeprazole |
| with or without | isoflurane | prednisone, prednisolone |
| sulbactam | isoniazid | ranitidine |
| atenolol | isradipine | rifabutin |
| azithromycin | influenza vaccine | roxithromycin |
| caffeine, | ketoconazole | sorbitol |
| dietary ingestion | lomefloxacin | (purgative doses do not |
| cefaclor | mebendazole | inhibit theophylline |
| co-trimoxazole | medroxyprogesterone | absorption) |
| (trimethoprim and | methylprednisolone | sucralfate |
| sulfamethoxazole) | metronidazole | terbutaline, systemic |
| diltiazem | metoprolol | terfenadine |
| dirithromycin | nadolol | tetracycline |
| enflurane | nifedipine | tocainide |
|
|
(Peak plasma concentration) |
(Extent of systemic exposure) |
|---|---|---|
| Erythromycin (500 mg every 8 hrs) |
+82% | +109% |
| Ketoconazole (400 mg once daily) |
+135% | +164% |
| Coadministered Drug |
Dosing Schedule |
|
Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
|
Risperidone Dose Recommendation |
|
|
Coadministered Drug |
Risperidone |
AUC |
Cm
a
x
|
|
| Enzyme (CYP2D6) Inhibitors |
|
|
|
|
|
| Fluoxetine |
20 mg/day |
2 or 3 mg twice daily |
1.4 |
1.5 |
Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine |
10 mg/day |
4 mg/day |
1.3 |
- |
Re-evaluate dosing. |
|
|
20 mg/day |
4 mg/day |
1.6 |
- |
Do not exceed 8 mg/day |
|
|
40 mg/day |
4 mg/day |
1.8 |
- |
|
| Enzyme (CYP3A/ PgP inducers) |
|
|
|
|
|
| Carbamazepine |
573 ± 168 mg/day |
3 mg twice daily |
0.51 |
0.55 |
Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors |
|
|
|
|
|
| Ranitidine |
150 mg twice daily |
1 mg single dose |
1.2 |
1.4 |
Dose adjustment not needed |
| Cimetidine |
400 mg twice daily |
1 mg single dose |
1.1 |
1.3 |
Dose adjustment not needed |
| Erythromycin |
500 mg four times daily |
1 mg single dose |
1.1 |
0.94 |
Dose adjustment not needed |
| Other Drugs |
|
|
|
|
|
| Amitriptyline |
50 mg twice daily |
3 mg twice daily |
1.2 |
1.1 |
Dose adjustment not needed |
|
|
| AED Co-administered |
AED Concentration |
Topiramate Concentration |
|---|---|---|
| a = Plasma concentration increased 25% in some patients, generally those on a b.i.d. dosing regimen of phenytoin. b = Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. AED = Antiepileptic drug. NE = Not Evaluated. TPM – Topiramate |
||
| Phenytoin | NC or 25% increasea | 48% decrease |
| Carbamazepine (CBZ) | NC 40% | decrease |
| CBZ epoxideb | NC | NE |
| Valproic acid | 11% decrease | 14% decrease |
| Phenobarbital | NC | NE |
| Primidone | NC | NE |
| Lamotrigine | NC at TPM doses up to 400 mg/day | 15% increase |
|
|
|
|
|
|
||
| Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz*, nevirapine* |
↓ lopinavir | KALETRA dose increase is recommended in all patients Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz. KALETRA should not be administered once daily in combination with efavirenz or nevirapine |
| Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine |
↑ lopinavir | Appropriate doses of the combination with respect to safety and efficacy have not been established. |
| Nucleoside Reverse Transcriptase Inhibitor: didanosine |
KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food). |
|
| Nucleoside Reverse Transcriptase Inhibitor: tenofovir |
↑ tenofovir | KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir. |
| Nucleoside Reverse Transcriptase Inhibitor: abacavir zidovudine |
↓ abacavir ↓ zidovudine |
KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown. |
| HIV-1 Protease Inhibitor: amprenavir* |
↑ amprenavir ↓ lopinavir |
KALETRA should not be administered once daily in combination with amprenavir |
| HIV-1 Protease Inhibitor: fosamprenavir/ritonavir |
↓ amprenavir ↓ lopinavir |
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor: indinavir* |
↑ indinavir | Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily |
| HIV-1 Protease Inhibitor: nelfinavir* |
↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir |
KALETRA should not be administered once daily in combination with nelfinavir |
| HIV-1 Protease Inhibitor: ritonavir* |
↑ lopinavir | Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor: saquinavir* |
↑ saquinavir | The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir. |
| HIV-1 Protease Inhibitor: tipranavir |
↓ lopinavir AUC and Cmin | KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily). |
| HIV CCR5 – Antagonist: maraviroc |
↑ maraviroc | Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry® (maraviroc). |
|
|
||
| Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), quinidine |
↑ antiarrhythmics | Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA. |
| Anticancer Agents: vincristine, vinblastine, dasatinib, nilotinib |
↑ anticancer agents | Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents. For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions. |
| Anticoagulant: warfarin |
Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored. | |
| Anticonvulsants: carbamazepine, phenobarbital, phenytoin |
↓ lopinavir ↓ phenytoin |
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA. |
| Antidepressant: bupropion |
↓ bupropion ↓ active metabolite, hydroxybupropion |
Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion. |
| Antidepressant: trazodone |
↑ trazodone | Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered. |
| Anti-infective: clarithromycin |
↑ clarithromycin | For patients with renal impairment, the following dosage adjustments should be considered: • For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. • For patients with CLCR < 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary. |
| Antifungals: ketoconazole*, itraconazole, voriconazole |
↑ ketoconazole ↑ itraconazole ↓ voriconazole |
High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended. Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients. |
| Anti-gout: colchicine |
↑ colchicine | Patients with renal or hepatic impairment should not be given colchicine with KALETRA. 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). |
| Antimycobacterial: rifabutin* |
↑ rifabutin and rifabutin metabolite | Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary. |
| Antimycobacterial: rifampin |
↓ lopinavir | May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone |
| Antiparasitic: atovaquone |
↓ atovaquone | Clinical significance is unknown; however, increase in atovaquone doses may be needed. |
| Benzodiazepines: parenterally administered midazolam | ↑ midazolam | Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam |
| Calcium Channel Blockers: dihydropyridine, felodipine, nifedipine, nicardipine |
↑ dihydropyridine calcium channel blockers | Caution is warranted and clinical monitoring of patients is recommended. |
| Contraceptive: ethinyl estradiol* |
↓ ethinyl estradiol | Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended. |
| Corticosteroid: dexamethasone |
↓ lopinavir | Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly. |
| disulfiram/metronidazole | KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole). | |
| Endothelin Receptor Antagonists: bosentan |
↑ bosentan |
In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. |
| HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin |
↑ atorvastatin ↑ rosuvastatin |
Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day. See Drugs with No Observed or Predicted Interactions with KALETRA |
| Immunosuppressants: cyclosporine, tacrolimus, rapamycin |
↑ immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA. |
| Inhaled Steroid: fluticasone |
↑ fluticasone | Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect. |
| Long-acting beta-adrenoceptor Agonist: salmeterol |
↑ salmeterol | Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
| Narcotic Analgesic: methadone* fentanyl |
↓ methadone ↑ fentanyl |
Dosage of methadone may need to be increased when co-administered with KALETRA. Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA. |
| PDE5 inhibitors: sildenafil, tadalafil, vardenafil |
↑ sildenafil ↑ tadalafil ↑ vardenafil |
Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA The following dose adjustments are recommended for use of tadalafil (Adcirca®) with KALETRA: In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: It is recommended not to exceed the following doses: • Sildenafil: 25 mg every 48 hours • Tadalafil: 10 mg every 72 hours • Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events. |
| * |
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|
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||
|
|
|||
| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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|
|
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| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone Iodide (including iodine- containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
|
|
|||
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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||
| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
|
|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
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|||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
|
|
|||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
|
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|||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
|
|
|
| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine, danazol | Do not exceed 10 mg simvastatin daily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Diltiazem | Do not exceed 40 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
|
|
|
| a Should be administered at least 4 hours prior to WELCHOL | |
|
b No significant alteration of warfarin drug levels with warfarin and WELCHOL coadministration in an |
|
| c Cyclosporine levels should be monitored and, based on theoretical grounds, cyclosporine should be administered at least 4 hours prior to WELCHOL. | |
| d Patients receiving concomitant metformin ER and colesevelam should be monitored for clinical response as is usual for the use of anti-diabetes drugs. | |
| Drugs with a known interaction with colesevelam: Decrease in exposure of coadministered drug | cyclosporinec, glimepiridea, glipizidea, glyburidea, levothyroxinea, olmesartan medoxomila, and oral contraceptives containing ethinyl estradiol and norethindronea |
| Drugs with a known interaction with colesevelam: Increase in exposure of coadministered drug | metformin extended release (ER)d |
| Drug(s) with postmarketing reports consistent with potential drug-drug interactions when coadministered with WELCHOL | phenytoina, warfarinb |
| Drugs that do not interact with colesevelam based on |
aspirin, atenolol, cephalexin, ciprofloxacin, digoxin, enalapril, fenofibrate, lovastatin, metformin, metoprolol, phenytoina, pioglitazone, rosiglitazone, quinidine, repaglinide, sitagliptin, valproic acid, verapamil, warfarinb |
|
AED Co-administered |
AED Concentration |
Topiramate Concentration |
|---|---|---|
| a = Plasma concentration
increased 25% in some patients, generally those on
a b.i.d. dosing regimen of phenytoin. b = Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. AED = Antiepileptic drug. NE = Not Evaluated. TPM – Topiramate |
||
| Phenytoin | NC or 25% increasea | 48% decrease |
| Carbamazepine (CBZ) | NC 40% | decrease |
| CBZ epoxideb | NC | NE |
| Valproic acid | 11% decrease | 14% decrease |
| Phenobarbital | NC | NE |
| Primidone | NC | NE |
| Lamotrigine | NC at TPM doses up to 400 mg/day | 15% increase |
| |
|
| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine,danazol | Do not exceed 10 mg simvastatindaily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Diltiazem | Do not exceed 40 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the oral solution formulation is taken within 2 hours of these products ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
|
|
|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
| AED Co-administered |
AED Concentration |
Topiramate Concentration |
| Phenytoin |
NC or 25% increasea
|
48% decrease |
| Carbamazepine (CBZ) |
NC |
40% decrease |
| CBZ epoxideb
|
NC |
NE |
| Valproic acid |
11% decrease |
14% decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NC at TPM doses up to 400 mg/day |
13% decrease |
|
|
|
|
|
|
|
|
||
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine |
Decreased lamotrigine levels approximately 50%. |
|
|
↓ levonorgestrel |
Decrease in levonorgestrel component by 19%. |
| Carbamazepine (CBZ) and CBZ epoxide |
↓ lamotrigine |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
|
|
? CBZ epoxide |
May increase CBZ epoxide levels |
| Phenobarbital/Primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40% |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40% |
| Valproate |
↑ lamotrigine |
Increased lamotrigine concentrations slightly more than 2-fold. |
|
|
? valproate |
Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
|
|
|
|
|---|---|---|
| ↑ Indicates increase. | ||
| ↓ Indicates decrease. | ||
| a Coadministration of didanosine with food decreases didanosine concentrations. Thus, although not studied, it is possible that coadministration with heavier meals could reduce didanosine concentrations further. | ||
| ganciclovir | ↑ didanosine concentration | If there is no suitable alternative to ganciclovir, then use in combination with VIDEX EC with caution. Monitor for didanosine-associated toxicity. |
| methadone | ↓ didanosine concentration | If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is VIDEX EC. Patients should be closely monitored for adequate clinical response when VIDEX EC is coadministered with methadone, including monitoring for changes in HIV RNA viral load. Do not coadminister methadone with VIDEX pediatric powder due to significant decreases in didanosine concentrations. |
| nelfinavir | No interaction 1 hour after didanosine | Administer nelfinavir 1 hour after VIDEX EC. |
| tenofovir disoproxil fumarate | ↑ didanosine concentration | A dose reduction of VIDEX EC to the
following dosage once daily taken together with tenofovir disoproxil fumarate
and a light meal (400 kcalories or less and 20% fat or less) or in the fasted
state is recommended.a
|
|
|
|
|
|---|---|---|
| ↑ Indicates increase. | ||
|
a Only
if other drugs are not available and if clearly indicated. If treatment with
life-sustaining drugs that cause pancreatic toxicity is required, suspension
of VIDEX EC is recommended [ |
||
|
b [ |
||
| Drugs that may cause pancreatic toxicity | ↑ risk of pancreatitis | Use only with extreme caution.a |
| Neurotoxic drugs | ↑ risk of neuropathy | Use with caution.b |
|
|
||
| albuterol, systemic and inhaled | hydrocortisone | nizatidine |
| amoxicillin | isoflurane | norfloxacin |
| ampicillin, with or without sulbactam | isoniazid | ofloxacin |
| atenolol | isradipine | omeprazole |
| azithromycin | influenza vaccine | prednisone, prednisolone |
| caffeine, dietary ingestion | ketoconazole | ranitidine |
| cefaclor | lomefloxacin | rifabutin |
| co-trimoxazole | mebendazole | roxithromycin |
| (trimethoprim and sulfamethoxazole) diltiazem | medroxyprogesterone | sorbitol |
| dirithromycin | methylprednisolone | (purgative doses do not inhibit theophylline absorption) |
| enflurane | metronidazole | sucralfate |
| famotidine | metoprolol | terbutaline, systemic |
| felodipine | nadolol | terfenadine |
| finasteride | nifedipine | tetracycline tocainide |
|
|
|
|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
|
|
|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
|
|
|
| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products. ( |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents |
Carefully monitor blood glucose ( |
|
|
|
| Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin |
| Amiodarone, verapamil, diltiazem |
Do not exceed 10 mg simvastatin daily |
| Amlodipine, ranolazine |
Do not exceed 20 mg simvastatin daily |
| Grapefruit juice |
Avoid large quantities of grapefruit juice (>1 quart daily) |
|
|
(mg/day) |
(mg/day) |
Concentration (Mean Change, 90% Confidence Interval) |
AED on MHD Concentration (Mean Change, 90% Confidence Interval) |
| Carbamazepine | 400-2000 | 900 | nc1 | 40% decrease [CI: 17% decrease, 57% decrease] |
| Phenobarbital | 100-150 | 600-1800 | 14% increase [CI: 2% increase, 24% increase] |
25% decrease [CI: 12% decrease, 51% decrease] |
| Phenytoin | 250-500 | 600-1800 >1200-2400 |
nc1,2
up to 40% increase3 [CI: 12% increase, 60% increase] |
30% decrease [CI: 3% decrease, 48% decrease] |
| Valproic acid | 400-2800 | 600-1800 | nc1 | 18% decrease [CI: 13% decrease, 40% decrease] |
| Concomitant Drug Class: Drug Name |
Effect on Concentration of Darunavir or Concomitant Drug | Clinical Comment |
|---|---|---|
|
|
||
| didanosine | ↔ darunavir ↔ didanosine |
Didanosine should be administered one hour before or two hours after PREZISTA/ritonavir (which are administered with food). |
|
|
||
| indinavir (The reference regimen for indinavir was indinavir/ritonavir 800/100 mg twice daily.) |
↑ darunavir ↑ indinavir |
The appropriate dose of indinavir in combination with PREZISTA/ritonavir has not been established. |
| lopinavir/ritonavir | ↓ darunavir ↔ lopinavir |
Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer lopinavir/ritonavir and PREZISTA, with or without ritonavir. |
| saquinavir | ↓ darunavir ↔ saquinavir |
Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer saquinavir and PREZISTA, with or without ritonavir. |
|
|
||
| Maraviroc | ↑ maraviroc | Maraviroc concentrations are increased when co-administered with PREZISTA/rtv. When used in combination with PREZISTA/rtv, the dose of maraviroc should be 150 mg twice daily. |
|
|
||
|
bepridil, lidocaine (systemic), quinidine, amiodarone, flecainide, propafenone |
↑ antiarrhythmics | Concentrations of these drugs may be increased when co-administered with PREZISTA/ritonavir. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when co-administered with PREZISTA/ritonavir. |
| digoxin | ↑ digoxin | The lowest dose of digoxin should initially be prescribed. The serum digoxin concentrations should be monitored and used for titration of digoxin dose to obtain the desired clinical effect. |
|
warfarin |
↓ warfarin ↔ darunavir |
Warfarin concentrations are decreased when co-administered with PREZISTA/ritonavir. It is recommended that the international normalized ratio (INR) be monitored when warfarin is combined with PREZISTA/ritonavir. |
|
carbamazepine |
↔ darunavir ↑ carbamazepine |
The dose of either darunavir/ritonavir or carbamazepine does not need to be adjusted when initiating co-administration with darunavir/ritonavir and carbamazepine. Clinical monitoring of carbamazepine concentrations and its dose titration is recommended to achieve the desired clinical response. |
|
phenobarbital, phenytoin |
↔ darunavir ↓ phenytoin ↓ phenobarbital |
Co-administration of PREZISTA/ritonavir may cause decrease in the steady-state concentrations of phenytoin and phenobarbital. Phenytoin and phenobarbital levels should be monitored when co-administering with PREZISTA/ritonavir. |
|
trazodone, desipramine |
↑ trazodone ↑ desipramine |
Concomitant use of trazodone or desipramine and PREZISTA/ritonavir may increase plasma concentrations of trazodone or desipramine which may lead to adverse events such as nausea, dizziness, hypotension and syncope. If trazodone or desipramine is used with PREZISTA/ritonavir, the combination should be used with caution and a lower dose of trazodone or desipramine should be considered. |
|
clarithromycin |
↔ darunavir ↑ clarithromycin |
No dose adjustment of the combination is required for patients with normal renal function. For patients with renal impairment, the following dose adjustments should be considered:
|
|
ketoconazole, itraconazole, voriconazole |
↑ ketoconazole ↑ darunavir ↑ itraconazole (not studied) ↓ voriconazole (not studied) |
Ketoconazole and itraconazole are potent inhibitors as well as substrates of CYP3A. Concomitant systemic use of ketoconazole, itraconazole, and darunavir/ritonavir may increase plasma concentration of darunavir. |
| Plasma concentrations of ketoconazole or itraconazole may be increased in the presence of darunavir/ritonavir. When co-administration is required, the daily dose of ketoconazole or itraconazole should not exceed 200 mg. | ||
| Plasma concentrations of voriconazole may be decreased in the presence of darunavir/ritonavir. Voriconazole should not be administered to patients receiving darunavir/ritonavir unless an assessment of the benefit/risk ratio justifies the use of voriconazole. | ||
|
colchicine |
↑ colchicine |
0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days. If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Patients with renal or hepatic impairment should not be given colchicine with PREZISTA/ritonavir. |
|
rifabutin |
↑ darunavir ↑ rifabutin ↑ 25- |
Dose reduction of rifabutin by at least 75% of the usual dose (300 mg once daily) is recommended (i.e., a maximum dose of 150 mg every other day). Increased monitoring for adverse events is warranted in patients receiving this combination and further dose reduction of rifabutin may be necessary. |
| The reference regimen for rifabutin was 300 mg once daily | ||
|
metoprolol, timolol |
↑ beta-blockers | Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir. |
|
parenterally administered midazolam |
↑ midazolam | Concomitant use of parenteral midazolam with PREZISTA/ritonavir may increase plasma concentrations of midazolam. Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Co-administration of oral midazolam with PREZISTA/ritonavir is CONTRAINDICATED. |
|
felodipine, nifedipine, nicardipine |
↑ calcium channel blockers | Plasma concentrations of calcium channel blockers (e.g., felodipine, nifedipine, nicardipine) may increase when PREZISTA/ritonavir are co-administered. Caution is warranted and clinical monitoring of patients is recommended. |
|
dexamethasone |
↓ darunavir | Systemic dexamethasone induces CYP3A and can thereby decrease darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA. |
|
fluticasone |
↑ fluticasone | Concomitant use of inhaled fluticasone and PREZISTA/ritonavir may increase plasma concentrations of fluticasone. Alternatives should be considered, particularly for long term use. |
|
bosentan |
↑ bosentan |
In patients who have been receiving PREZISTA/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of PREZISTA/ritonavir. After at least 10 days following the initiation of PREZISTA/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. |
|
pravastatin, atorvastatin, rosuvastatin |
↑ pravastatin ↑ atorvastatin ↑ rosuvastatin |
Use the lowest possible dose of atorvastatin, pravastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as fluvastatin in combination with PREZISTA/ritonavir. |
|
cyclosporine, tacrolimus, sirolimus |
↑ immunosuppressants | Plasma concentrations of cyclosporine, tacrolimus or sirolimus may be increased when co-administered with PREZISTA/ritonavir. Therapeutic concentration monitoring of the immunosuppressive agent is recommended when co-administered with PREZISTA/ritonavir. |
|
salmeterol |
↑ salmeterol | Concurrent administration of salmeterol and PREZISTA/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
|
methadone, buprenorphine, buprenorphine/naloxone |
↓ methadone ↔ buprenorphine, naloxone ↑ norbuprenorphine (metabolite) |
No adjustment of methadone dosage is required when initiating co-administration of PREZISTA/ritonavir. However, clinical monitoring is recommended as the dose of methadone during maintenance therapy may need to be adjusted in some patients. No dose adjustment for buprenorphine or buprenorphine/naloxone is required with concurrent administration of PREZISTA/ritonavir. Clinical monitoring is recommended if PREZISTA/ritonavir and buprenorphine or buprenorphine/naloxone are coadministered. |
|
risperidone, thioridazine |
↑ neuroleptics | A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir. |
|
ethinyl estradiol, norethindrone |
↓ ethinyl estradiol ↓ norethindrone |
Plasma concentrations of ethinyl estradiol are decreased due to induction of its metabolism by ritonavir. Alternative methods of nonhormonal contraception are recommended. |
|
sildenafil, vardenafil, tadalafil |
↑ PDE-5 inhibitors (only the use of sildenafil at doses used for treatment of erectile dysfunction has been studied with PREZISTA/ritonavir) |
Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg dose in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours can be used with increased monitoring for PDE-5 inhibitor-associated adverse events. |
|
sertraline, paroxetine |
↔ darunavir ↓ sertraline ↓ paroxetine |
If sertraline or paroxetine is co-administered with PREZISTA/ritonavir, the recommended approach is a careful dose titration of the SSRI based on a clinical assessment of antidepressant response. In addition, patients on a stable dose of sertraline or paroxetine who start treatment with PREZISTA/ritonavir should be monitored for antidepressant response. |
|
|
|
| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine, danazol | Do not exceed 10 mg simvastatin daily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Diltiazem | Do not exceed 40 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (> 1 quart daily) |
| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine |
Do not coadminister the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding |
| Antidiabetic agents |
Carefully monitor blood glucose |
|
Risk of Myopathy/Rhabdomyolysis ( |
|
| Interacting Agents | Prescribing Recommendations |
| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol, verapamil, diltiazem |
Contraindicated with SIMCOR |
| Amiodarone, amlodipine, ranolazine | Do not exceed 1000/20 mg SIMCOR daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
|
|
|
| Aspirin w/anti-inflammatory agents |
ulcerogenic effects. |
| Butalbital w/coumarin anticoagulants |
anticoagulant because of increased metabolism resulting from enzyme induction. |
| Butalbital w/tricyclic antidepressants |
levels of the antidepressant. |
|
|
|
|
|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
|
|
|
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
| Alpha-Blocker | Simultaneous dosing of Vardenafil 5 mg and Alpha-Blocker, Placebo-Subtracted |
Dosing of Vardenafil 5 mg and Alpha-Blocker Separated by 6 Hours, Placebo-Subtracted |
|
| Terazosin 5 or 10 mg daily |
Standing SBP | -3 (-6.7, 0.1) | -4 (-7.4, -0.5) |
| Supine SBP | -4 (-6.7, -0.5) | -4 (-7.1, -0.7) | |
| Tamsulosin 0.4 mg daily |
Standing SBP Supine SBP |
-6 (-9.9, -2.1) -4 (-7.0, -0.8) |
-4 (-8.3, -0.5) -5 (-7.9, -1.7) |
| Vardenafil 10 mg Placebo-subtracted |
Vardenafil 20 mg Placebo-subtracted |
|
| Standing SBP | -4 (-6.8, -0.3) | -4 (-6.8, -1.4) |
| Supine SBP | -5 (-8.2, -0.8) | -4 (-6.3, -1.8) |
| Concomitant Drug Class or Food | Noted or anticipated Outcome | Clinical Comment |
|---|---|---|
|
atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin |
Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality) | Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy. |
|
fibrates, gemfibrozil |
||
|
digoxin |
P-gp substrate; rhabdomyolysis has been reported |
|
|
|
|
| Atazanavir/Ritonavir | ↓ Atazanavir ↑ Nevirapine |
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure. |
| Clarithromycin | ↓ Clarithromycin ↑ 14-OH clarithromycin |
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against |
| Efavirenz | ↓ Efavirenz | There has been no determination of appropriate doses for the safe and effective use of this combination [ |
| Ethinyl estradiol andNorethindrone | ↓ Ethinyl estradiol ↓ Norethindrone |
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended |
| Fluconazole | ↑Nevirapine | Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine- associated adverse events. |
| Fosamprenavir | ↓Amprenavir ↑Nevirapine |
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. |
| Fosamprenavir/Ritonavir | ↓Amprenavir ↑Nevirapine |
No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. |
| Indinavir | ↓ Indinavir | Appropriate doses for this combination are not established, but an increase in the dosage of indinavir may be required. |
| Ketoconazole | ↓ Ketoconazole | Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. |
| Lopinavir/Ritonavir | ↓Lopinavir | A dose increase of lopinavir/ritonavir tablets to 500/125 mg twice-daily is recommended when used in combination with nevirapine.A dose increase of lopinavir/ritonavir oral solution to 533/133 mg twice daily with food is recommended in combination with nevirapine. In children 6 months to 12 years of age receiving lopinavir/ritonavir solution, consideration should be given to increasing the dose of lopinavir/ritonavir to 13/3.25 mg/kg for those 7 to <15 kg; 11/2.75 mg/kg for those 15 to 45 kg; up to a maximum dose of 533/133 mg twice daily. Refer to the lopinavir/ritonavir package insert for complete pediatric dosing instructions when lopinavir/ritonavir tablets are used in combination with nevirapine. |
| Methadone | ↓ Methadone | Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone- maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. |
| Nelfinavir | ↓Nelfinavir M8 Metabolite ↓Nelfinavir Cmin |
The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established. |
| Rifabutin | ↑Rifabutin | Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. |
| Rifampin | ↓ Nevirapine | Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead. |
| Saquinavir /Ritonavir | The interaction between Nevirapine and saquinavir/ritonavir has not been evaluated | The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established. |
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| Antiarrhythmics | Amiodarone, disopyramide, lidocaine | Plasma concentrations may be decreased. |
| Anticonvulsants | Carbamazepine, clonazepam, ethosuximide | Plasma concentrations may be decreased. |
| Antifungals | Itraconazole | Plasma concentrations of some azole antifungals may be decreased. Nevirapine and itraconazole should not be administered concomitantly due to a potential decrease in itraconazole plasma concentrations. |
| Calcium channel blockers | Diltiazem, nifedipine, verapamil | Plasma concentrations may be decreased. |
| Cancer chemotherapy | Cyclophosphamide | Plasma concentrations may be decreased. |
| Ergot alkaloids | Ergotamine | Plasma concentrations may be decreased. |
| Immunosuppressants | Cyclosporin, tacrolimus, sirolimus | Plasma concentrations may be decreased. |
| Motility agents | Cisapride | Plasma concentrations may be decreased. |
| Opiate agonists | Fentanyl | Plasma concentrations may be decreased. |
| Antithrombotics | Warfarin | Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended. |
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|
(mg/day) |
Dose |
Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval) |
AED on MHD Concentration (Mean Change, 90% Confidence Interval) |
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57% decrease] |
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24% increase] |
51% decrease] |
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48% decrease] |
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60% increase] |
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40% decrease] |
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| Concomitant Drug |
Effect on Concentration of Lamotrigine or Concomitant Drug |
Clinical Comment |
| Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine ↓ levonorgestrel |
Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%. |
| Carbamazepine (CBZ) and CBZ epoxide |
↓ lamotrigine ? CBZ epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase CBZ epoxide levels |
| Phenobarbital/Primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40%. |
| Valproate |
↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
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| Amphetamines, cocaine, other sympathomimetic agents | Additive hypertension, tachycardia, possibly cardiotoxicity |
| Atropine, scopolamine, antihistamines, other anticholinergic agents | Additive or super-additive tachycardia, drowsiness |
| Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants | Additive tachycardia, hypertension, drowsiness |
| Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants | Additive drowsiness and CNS depression |
| Disulfiram | A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge |
| Fluoxetine | A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days |
| Antipyrine, barbiturates | Decreased clearance of these agents,presumably via competitive inhibition of metabolism |
| Theophylline | Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco |
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| Enzyme | Inhibitors | Inducers |
|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
| Drug Class | Specific Drugs |
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
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|||
| DRUG | DESCRIPTION OF INTERACTION | ||
| Sulfonylureas | Hypoglycemia potentiated. | ||
| Methotrexate | Decreases tubular reabsorption; clinical toxicity from methotrexate can result. | ||
| Oral Anticoagulants | Increased bleeding. | ||
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|||
| DRUG | DESCRIPTION OF INTERACTION | ||
| Corticosteroids | Decreases plasma salicylate level; tapering doses of steroids may promote salicylism. | ||
| Acidifying Agents | Increases plasma salicylate levels. | ||
| Alkanizing Agents | Decreased plasma salicylate levels. | ||
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| DRUG | DESCRIPTION OF INTERACTION | ||
| Heparin | Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients. | ||
| Pyrazinamide | Inhibits pyrazinamide-induced hyperuricemia. | ||
| Uricosuric Agents | Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited. | ||
| The following alterations of laboratory tests have been reported during salicylate therapy: | |||
| LABORATORY TESTS | EFFECT OF SALICYLATES | ||
| Thyroid Function | Decreased PBI; increased t3 uptake. | ||
| Urinary Sugar | False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.). | ||
| 5-Hydroxyindole acetic acid | False negative with fluorometric test. | ||
| Acetone ketone bodies | False positive FeCI3 in Gerhardt reaction; red color persists with boiling. | ||
| 17-OH corticosteroids | False reduced values with >4.8g q.d. salicylate. | ||
| Vanilmandelic acid | False reduced values. | ||
| Uric Acid | May increase or decrease depending on dose. | ||
| Prothrombin | Decreased levels; slightly increased prothrombin time. | ||
| Alpha-Blocker | Simultaneous dosing of Vardenafil 5 mg and Alpha-Blocker, Placebo-Subtracted |
Dosing of Vardenafil 5 mg and Alpha-Blocker Separated by 6 Hours, Placebo-Subtracted |
|
| Terazosin 5 or 10 mg daily |
Standing SBP | -3 (-6.7, 0.1) | -4 (-7.4, -0.5) |
| Supine SBP | -4 (-6.7, -0.5) | -4 (-7.1, -0.7) | |
| Tamsulosin 0.4 mg daily |
Standing SBP Supine SBP |
-6 (-9.9, -2.1) -4 (-7.0, -0.8) |
-4 (-8.3, -0.5) -5 (-7.9, -1.7) |
| Vardenafil 10 mg Placebo-subtracted |
Vardenafil 20 mg Placebo-subtracted |
|
| Standing SBP | -4 (-6.8, -0.3) | -4 (-6.8, -1.4) |
| Supine SBP | -5 (-8.2, -0.8) | -4 (-6.3, -1.8) |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
|
Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide |
|
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels. | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate |
|
Increased lamotrigine concentrations slightly more than 2 fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
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|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
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|
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
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| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of this product. |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding |
| Antidiabetic agents |
Carefully monitor blood glucose |
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| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid grapefruit juice |
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|
Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
|
|
Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C Protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
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| AED Co-administered |
AED Concentration |
Topiramate Concentration |
| Phenytoin |
NC or 25% increasea
|
48% decrease |
| Carbamazepine (CBZ) |
NC |
40% decrease |
| CBZ epoxideb
|
NC |
NE |
| Valproic acid |
11% decrease |
14% decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NC at TPM doses up to 400 mg/day |
13% decrease |
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| Multivalent cation-containing products including antacids, metal cations or didanosine |
Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents |
Carefully monitor blood glucose ( |
| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
|
|---|---|
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) | Do not exceed 40 mg atorvastatin daily |
| Concomitant Drug Class: Drug Name | Effect on Concentration | Clinical Comment |
|---|---|---|
|
antacids (e.g., aluminium, magnesium hydroxide, or calcium carbonate) |
↔ rilpivirine (antacids taken at least 2 hours before or at least 4 hours after rilpivirine) ↓ rilpivirine (concomitant intake) |
The combination of COMPLERA and antacids should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). Antacids should only be administered either at least 2 hours before or at least 4 hours after COMPLERA. |
|
fluconazole itraconazole ketoconazole posaconazole voriconazole |
↑ rilpivirine ↓ ketoconazole |
Concomitant use of COMPLERA with azole antifungal agents may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when COMPLERA is coadministered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are coadministered with COMPLERA. |
|
cimetidine famotidine nizatidine ranitidine |
↔ rilpivirine (famotidine taken 12 hours before rilpivirine or 4 hours after rilpivirine) ↓ rilpivirine (famotidine taken 2 hours before rilpivirine) |
The combination of COMPLERA and H2-receptor antagonists should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). H2-receptor antagonists should only be administered at least 12 hours before or at least 4 hours after COMPLERA. |
|
clarithromycin erythromycin telithromycin |
↑ rilpivirine ↔ clarithromycin ↔ erythromycin ↔ telithromycin |
Concomitant use of COMPLERA with clarithromycin, erythromycin or telithromycin may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Where possible, alternatives such as azithromycin should be considered. |
|
methadone |
↓ R(–) methadone ↓ S(+) methadone ↔ rilpivirine ↔ methadone |
No dose adjustments are required when initiating coadministration of methadone with COMPLERA. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients. |
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|
| Atazanavir/Ritonavir | ↓ Atazanavir ↑ Nevirapine |
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure. |
| Clarithromycin | ↓ Clarithromycin ↑ 14-OH clarithromycin |
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against |
| Efavirenz | ↓ Efavirenz | There has been no determination of appropriate doses for the safe and effective use of this combination [ |
| Ethinyl estradiol and Norethindrone | ↓ Ethinyl estradiol ↓ Norethindrone |
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended. |
| Fluconazole | ↑Nevirapine | Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events. |
| Fosamprenavir | ↓Amprenavir ↑Nevirapine |
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. |
| Fosamprenavir/Ritonavir | ↓Amprenavir ↑Nevirapine |
No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. |
| Indinavir | ↓ Indinavir | Appropriate doses for this combination are not established, but an increase in the dosage of indinavir may be required. |
| Ketoconazole | ↓ Ketoconazole | Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. |
| Lopinavir/Ritonavir | ↓Lopinavir | A dose increase of lopinavir/ritonavir tablets to 500/125 mg twice-daily is recommended when used in combination with nevirapine. A dose increase of lopinavir/ritonavir oral solution to 533/133 mg twice daily with food is recommended in combination with nevirapine. In children 6 months to 12 years of age receiving lopinavir/ritonavir solution, consideration should be given to increasing the dose of lopinavir/ritonavir to 13/3.25 mg/kg for those 7 to <15 kg; 11/2.75 mg/kg for those 15 to 45 kg; up to a maximum dose of 533/133 mg twice daily. Refer to the lopinavir/ritonavir package insert for complete pediatric dosing instructions when lopinavir/ritonavir tablets are used in combination with nevirapine. |
| Methadone | ↓ Methadone | Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. |
| Nelfinavir | ↓Nelfinavir M8 Metabolite ↓Nelfinavir Cmin |
The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established. |
| Rifabutin | ↑Rifabutin | Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. |
| Rifampin | ↓ Nevirapine | Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead. |
| Saquinavir/ritonavir | The interaction between nevirapine and saquinavir/ritonavir has not been evaluated | The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established. |
|
|
||
|
|
Examples of Drugs | |
|---|---|---|
| Antiarrhythmics | Amiodarone, disopyramide, lidocaine | Plasma concentrations may be decreased. |
| Anticonvulsants | Carbamazepine, clonazepam, ethosuximide | Plasma concentrations may be decreased. |
| Antifungals | Itraconazole | Plasma concentrations of some azole antifungals may be decreased. Nevirapine and itraconazole should not be administered concomitantly due to a potential decrease in itraconazole plasma concentrations. |
| Calcium channel blockers | Diltiazem, nifedipine, verapamil | Plasma concentrations may be decreased. |
| Cancer chemotherapy | Cyclophosphamide | Plasma concentrations may be decreased. |
| Ergot alkaloids | Ergotamine | Plasma concentrations may be decreased. |
| Immunosuppressants | Cyclosporin, tacrolimus, sirolimus | Plasma concentrations may be decreased. |
| Motility agents | Cisapride | Plasma concentrations may be decreased. |
| Opiate agonists | Fentanyl | Plasma concentrations may be decreased. |
| Antithrombotics | Warfarin | Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended. |
| DRUG | DESCRIPTION OF INTERACTION |
| Sulfonylureas | Hypoglycemia potentiated. |
| Methotrexate | Decreases tubular reabsorption; clinical toxicity from methotrexate can result. |
|
|
Increased bleeding. |
| DRUG | DESCRIPTION OF INTERACTION |
| Corticosteroids | Decreases plasma salicylate level; tapering doses of steroids may promote salicylism. |
| Acidifying Agents | Increases plasma salicylate level. |
| Alkanizing Agents | Decreased plasma salicylate levels. |
| DRUG | DESCRIPTION OF INTERACTION |
|
|
|
| Pyrazinamide | Inhibits pyrazinamide induced hyperuricemia. |
| Uricosuric Agents | Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited. |
| LABORATORY TESTS | EFFECT OF SALICYLATES |
| Thyroid Function | Decreased PBI; increased T3 uptake. |
| Urinary Sugar | False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.). |
| 5-Hydroxyindole acetic acid | False negative with fluorometric test. |
| Acetone, ketone bodies | False positive FeCl3 in Gerhardt reaction; red color persists with boiling. |
| 17-OH corticosteroids | False reduced values with >4.8g q.d. salicylate. |
| Vanilmandelic acid | False reduced values. |
| Uric acid | May increase or decrease depending on dose. |
| Prothrombin | Decreased levels; slightly increased prothrombin time. |
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| Tolbutamide; Sulfonylureas | Hypoglycemia potentiated |
| Methotrexate | Decreases tubular reabsorption; clinical toxicity from methotrexate can result |
| Oral Anticoagulant | Increased bleeding |
|
|
|
| Corticosteroids | Decreases plasma salicylate level; Tapering doses of steroids may promote salicylism |
| Ammonium Sulfate | Increases plasma salicylate level |
|
|
|
| Heparin | Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients |
| Pyrazinamide | Inhibits pyrazinamide-induced hyperuricemia |
| Uricosuric Agents | Effect of probenecid, sulfinpyrazone and phenylbutazone inhibited |
|
|
|
| Thyroid Function | Decreased PBI; increased T3 uptake |
| Urinary Sugar | False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5 g qd) |
| 5 Hydroxyindole acetic acid | False negative with fluorometric test |
| Acetone, Ketone Bodies | False positive FeCl3 in Gerhardt reaction; red color persists with boiling |
| 17-OH corticosteroids | False reduced values with >4.8 g qd salicylate |
| Vanilmandelic Acid | False reduced values |
| Uric Acid | May increase or decrease depending on dose |
| Prothrombin | Decreased levels; slightly increased prothrombin time |
|
|
|
|
|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
|
|
|
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
|
|
|
|
|
Avoid atorvastatin
|
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
|
|
Do not exceed 20 mg atorvastatin daily
|
| HIV protease inhibitor (nelfinavir) | Do not exceed 40 mg atorvastatin daily |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin |
|
|
|
fibrates, gemfibrozil |
||
|
digoxin |
|
| Enzyme | Inhibitors | Inducers |
|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
| Drug Class | Specific Drugs |
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
|
|
|
|
|
|
||
| Phenytoin |
NC or 25% increasea
|
48% decrease |
| Carbamazepine (CBZ) |
NC |
40% decrease |
| CBZ epoxideb
|
NC |
NE |
| Valproic acid |
11% decrease |
14% decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NC at TPM doses up to 400 mg/day |
13% decrease |
|
|
|
|
|
|
|
Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
|
|
|
|
|
|
|
Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
|
|
|
|
Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
|
|
|
|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function. |
|
|
|
|
|
|
|
Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
|
Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4 . Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
|
|
|
|
|
|
|
Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
|
|
|
|
Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
|
|
|
|
- Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
|
- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
|
- Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
|
- Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
|
- Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
|
- (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
|
Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
|
|
|
|
| CYP2C9 |
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast |
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 |
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton |
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 |
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton |
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
|
|
|
| Anticoagulants |
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents |
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents |
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors |
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
|
|
|||||
| Coadministered Drug | Dose of Coadministered Drug | Dose of Azithromycin | n | Ratio (with/without azithromycin) of Coadministered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00 | |
| Mean Cmax | Mean AUC | ||||
| Atorvastatin | 10 mg/day x 8 days | 500 mg/day PO on days 6 to 8 | 12 | 0.83 (0.63 to 1.08) | 1.01 (0.81 to 1.25) |
| Carbamazepine | 200 mg/day x 2 days, then 200 mg BID x 18 days | 500 mg/day PO for days 16 to 18 | 7 | 0.97 (0.88 to 1.06) | 0.96 (0.88 to 1.06) |
| Cetirizine | 20 mg/day x 11 days | 500 mg PO on day 7, then 250 mg/day on days 8 to 11 | 14 | 1.03 (0.93 to 1.14) | 1.02 (0.92 to 1.13) |
| Didanosine | 200 mg PO BID x 21 days | 1,200 mg/day PO on days 8 to 21 | 6 | 1.44 (0.85 to 2.43) | 1.14 (0.83 to 1.57) |
| Efavirenz | 400 mg/day x 7 days | 600 mg PO on day 7 | 14 | 1.04* | 0.95* |
| Fluconazole | 200 mg PO single dose | 1,200 mg PO single dose | 18 | 1.04 (0.98 to 1.11) | 1.01 (0.97 to 1.05) |
| Indinavir | 800 mg TID x 5 days | 1,200 mg PO on day 5 | 18 | 0.96 (0.86 to 1.08) | 0.90 (0.81 to 1.00) |
| Midazolam | 15 mg PO on day 3 | 500 mg/day PO x 3 days | 12 | 1.27 (0.89 to 1.81) | 1.26 (1.01 to 1.56) |
| Nelfinavir | 750 mg TID x 11 days | 1,200 mg PO on day 9 | 14 | 0.90 (0.81 to 1.01) | 0.85 (0.78 to 0.93) |
| Rifabutin | 300 mg/day x 10 days | 500 mg PO on day 1, then 250 mg/day on days 2 to 10 | 6 | See footnote below | NA |
| Sildenafil | 100 mg on days 1 and 4 | 500 mg/day PO x 3 days | 12 | 1.16 (0.86 to 1.57) | 0.92 (0.75 to 1.12) |
| Theophylline | 4 mg/kg IV on days 1, 11, 25 | 500 mg PO on day 7, 250 mg/day on days 8 to 11 | 10 | 1.19 (1.02 to 1.40) | 1.02 (0.86 to 1.22) |
| Theophylline | 300 mg PO BID x 15 days | 500 mg PO on day 6, then 250 mg/day on days 7 to 10 | 8 | 1.09 (0.92 to 1.29) | 1.08 (0.89 to 1.31) |
| Triazolam | 0.125 mg on day 2 | 500 mg PO on day 1, then 250 mg/day on day 2 | 12 | 1.06* | 1.02* |
| Trimethoprim/ Sulfamethoxazole | 160 mg/800 mg/day PO x 7 days | 1,200 mg PO on day 7 | 12 | 0.85 (0.75 to 0.97)/0.90 (0.78 to 1.03) | 0.87 (0.80 to 0.95)/0.96 (0.88 to 1.03) |
| Zidovudine | 500 mg/day PO x 21 days | 600 mg/day PO x 14 days | 5 | 1.12 (0.42 to 3.02) | 0.94 (0.52 to 1.70) |
| Zidovudine | 500 mg/day PO x 21 days | 1,200 mg/day PO x 14 days | 4 | 1.31 (0.43 to 3.97) | 1.30 (0.69 to 2.43) |
|
|
|||||
| Coadministered Drug | Dose of Coadministered Drug | Dose of Azithromycin | n | Ratio (with/without coadministered drug) of Azithromycin Pharmacokinetic Parameters (90% CI); No Effect = 1.00 | |
| Mean Cmax | Mean AUC | ||||
| Efavirenz | 400 mg/day x 7 days | 600 mg PO on day 7 | 14 | 1.22 (1.04 to 1.42) | 0.92* |
| Fluconazole | 200 mg PO single dose | 1,200 mg PO single dose | 18 | 0.82 (0.66 to 1.02) | 1.07 (0.94 to 1.22) |
| Nelfinavir | 750 mg TID x 11 days | 1,200 mg PO on day 9 | 14 | 2.36 (1.77 to 3.15) | 2.12 (1.80 to 2.50) |
| Rifabutin | 300 mg/day x 10 days | 500 mg PO on day 1, then 250 mg/day on days 2 to 10 | 6 | See footnote below | NA |
|
|
|
|
|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
|
|
|
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
|
|
|
|
|
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
|
|
|
|
|
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
|
|
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
|
|
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
|
|
Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
|
|
Thereapy wih interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
|
|
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
(Peak plasma concentration) |
(Extent of systemic exposure) |
|---|---|---|
| Erythromycin (500 mg every 8 hrs) |
+82% | +109% |
| Ketoconazole (400 mg once daily) |
+135% | +164% |
|
Drug |
|
(Risperidone + 9- Hydroxy-Risperidone (Ratio |
Dose Recommendation |
||
|
Drug |
|
|
|
||
|
(CYP2D6) Inhibitors |
|||||
|
|
|
twice daily |
|
|
dosing. Do not exceed 8 mg/day |
|
|
|
|
|
|
dosing. Do not exceed 8 mg/day |
|
|
|
|
|
||
|
|
|
|
|
||
|
(CYP3A/PgP inducers) |
|||||
|
|
mg/day |
daily |
|
|
upwards. Do not exceed twice the patient’s usual dose |
|
(CYP3A) Inhibitors |
|||||
|
|
daily |
dose |
|
|
not needed |
|
|
daily |
dose |
|
|
not needed |
|
|
daily |
dose |
|
|
not needed |
|
|
|||||
|
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daily |
daily |
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not needed |
| Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) | VIAGRA 25 mg |
|---|---|
| Supine | 7.4 (-0.9, 15.7) |
| Standing | 6.0 (-0.8, 12.8) |
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| Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) | VIAGRA 100 mg |
|---|---|
| Supine | 7.9 (4.6, 11.1) |
| Standing |
4.3 (-1.8,10.3) |
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| ciprofloxacin | melphalan | azapropazon | cimetidine |
| gentamicin | colchicine | ranitidine | |
| tobramycin |
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diclofenac | |
| vancomycin | amphotericin B | naproxen |
|
| trimethoprim | ketoconazole | sulindac | tacrolimus |
| with | |||
| sulfamethoxazole |
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| fibric acid derivatives | |||
| (e.g., bezafibrate, | |||
| fenofibrate) |
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| Interacting Agents | Prescribing Recommendations |
|---|---|
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
|
|
|
| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid grapefruit juice |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
|
Decreased Lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide |
|
Addition of carbamazepine decreases Lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels. | |
| Phenobarbital/Primidone | ↓ Lamotrigine | Decreased Lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ Lamotrigine | Decreased Lamotrigine concentration approximately 40%. |
| Rifampin | ↓ Lamotrigine | Decreased Lamotrigine AUC approximately 40%. |
| Valproate |
|
Increased Lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
| Concomitant Drug Class: Drug Name |
Effect on Concentration of Etravirine or Concomitant Drug | Clinical Comment |
|---|---|---|
|
|
||
| efavirenz nevirapine |
↓ etravirine | Combining two NNRTIs has not been shown to be beneficial. Concomitant use of INTELENCE® with efavirenz or nevirapine may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and other NNRTIs should not be co-administered. |
| delavirdine | ↑ etravirine | Combining two NNRTIs has not been shown to be beneficial. INTELENCE® and delavirdine should not be co-administered. |
| rilpivirine | ↓ rilpivirine ↔ etravirine |
Combining two NNRTIs has not been shown to be beneficial. INTELENCE® and rilpivirine should not be coadministered. |
|
|
||
| atazanavir (without ritonavir) |
↓ atazanavir | Concomitant use of INTELENCE® with atazanavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of atazanavir. INTELENCE® should not be co-administered with atazanavir without low-dose ritonavir. |
| atazanavir/ritonavir |
↓ atazanavir ↑ etravirine |
Concomitant use of INTELENCE® with atazanavir/ritonavir may cause a significant decrease in atazanavir Cmin and loss of therapeutic effect of atazanavir. In addition, the mean systemic exposure (AUC) of etravirine after co-administration of INTELENCE® with atazanavir/ritonavir is anticipated to be higher than the mean systemic exposure of etravirine observed in the Phase 3 trials after co-administration of INTELENCE® and darunavir/ritonavir (as part of the background regimen). INTELENCE® and atazanavir/ritonavir should not be co-administered. |
| darunavir/ritonavir |
↓ etravirine | The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE® was co-administered with darunavir/ritonavir. Because all subjects in the Phase 3 trials received darunavir/ritonavir as part of the background regimen and etravirine exposures from these trials were determined to be safe and effective, INTELENCE® and darunavir/ritonavir can be co-administered without dose adjustments. |
| fosamprenavir (without ritonavir) |
↑ amprenavir | Concomitant use of INTELENCE® with fosamprenavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of amprenavir. INTELENCE® should not be co-administered with fosamprenavir without low-dose ritonavir. |
| fosamprenavir/ritonavir |
↑ amprenavir | Due to a significant increase in the systemic exposure of amprenavir, the appropriate doses of the combination of INTELENCE® and fosamprenavir/ritonavir have not been established. INTELENCE® and fosamprenavir/ritonavir should not be co-administered. |
| indinavir (without ritonavir) |
↓ indinavir | Concomitant use of INTELENCE® with indinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of indinavir. INTELENCE® should not be co-administered with indinavir without low-dose ritonavir. |
| lopinavir/ritonavir |
↓ etravirine | The mean systemic exposure (AUC) of etravirine was reduced after co-administration of INTELENCE® with lopinavir/ritonavir (tablet). Because the reduction in the mean systemic exposures of etravirine in the presence of lopinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE® and lopinavir/ritonavir can be co-administered without dose adjustments. |
| nelfinavir (without ritonavir) |
↑ nelfinavir | Concomitant use of INTELENCE® with nelfinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of nelfinavir. INTELENCE® should not be co-administered with nelfinavir without low-dose ritonavir. |
| ritonavir |
↓ etravirine | Concomitant use of INTELENCE® with ritonavir 600 mg twice daily may cause a significant decrease in the plasma concentration of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and ritonavir 600 mg twice daily should not be co-administered. |
| saquinavir/ritonavir |
↓ etravirine | The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE® was co-administered with saquinavir/ritonavir. Because the reduction in the mean systemic exposures of etravirine in the presence of saquinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE® and saquinavir/ritonavir can be co-administered without dose adjustments. |
| tipranavir/ritonavir |
↓ etravirine | Concomitant use of INTELENCE® with tipranavir/ritonavir may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and tipranavir/ritonavir should not be co-administered. |
|
|
||
| maraviroc |
↔ etravirine ↓ maraviroc |
When INTELENCE® is co-administered with maraviroc in the absence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 600 mg twice daily. No dose adjustment of INTELENCE® is needed. |
| maraviroc/darunavir/ritonavir |
↔ etravirine ↑ maraviroc |
When INTELENCE® is co-administered with maraviroc in the presence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 150 mg twice daily. No dose adjustment of INTELENCE® is needed. |
|
|
||
|
digoxin |
↔ etravirine ↑ digoxin |
For patients who are initiating a combination of INTELENCE® and digoxin, the lowest dose of digoxin should initially be prescribed. For patients on a stable digoxin regimen and initiating INTELENCE®, no dose adjustment of either INTELENCE® or digoxin is needed. The serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect. |
| amiodarone, bepridil, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine |
↓ antiarrhythmics | Concentrations of these antiarrhythmics may be decreased when co-administered with INTELENCE®. INTELENCE® and antiarrhythmics should be co-administered with caution. Drug concentration monitoring is recommended, if available. |
|
warfarin |
↑ anticoagulants | Warfarin concentrations may be increased when co-administered with INTELENCE®. The international normalized ratio (INR) should be monitored when warfarin is combined with INTELENCE®. |
|
carbamazepine, phenobarbital, phenytoin |
↓ etravirine | Carbamazepine, phenobarbital and phenytoin are inducers of CYP450 enzymes. INTELENCE® should not be used in combination with carbamazepine, phenobarbital, or phenytoin as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®. |
|
fluconazole voriconazole |
↑ etravirine ↔ fluconazole ↑ voriconazole |
Co-administration of etravirine and fluconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and fluconazole should be co-administered with caution. No dose adjustment of INTELENCE® or fluconazole is needed. |
| Co-administration of etravirine and voriconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and voriconazole should be co-administered with caution. No dose adjustment of INTELENCE® or voriconazole is needed. | ||
|
itraconazole, ketoconazole, posaconazole |
↑ etravirine ↓ itraconazole ↓ ketoconazole ↔ posaconazole |
Posaconazole, a potent inhibitor of CYP3A4, may increase plasma concentrations of etravirine. Itraconazole and ketoconazole are potent inhibitors as well as substrates of CYP3A4. Concomitant systemic use of itraconazole or ketoconazole and INTELENCE® may increase plasma concentrations of etravirine. Simultaneously, plasma concentrations of itraconazole or ketoconazole may be decreased by INTELENCE®. Dose adjustments for itraconazole, ketoconazole or posaconazole may be necessary depending on the other co-administered drugs. |
|
clarithromycin |
↑ etravirine ↓ clarithromycin ↑ 14-OH-clarithromycin |
Clarithromycin exposure was decreased by INTELENCE®; however, concentrations of the active metabolite, 14-hydroxy-clarithromycin, were increased. Because 14-hydroxy-clarithromycin has reduced activity against |
|
artemether/lumefantrine |
↔ etravirine ↓ artemether ↓ dihydroartemisinin ↓ lumefantrine |
Caution is warranted when co-administering INTELENCE® and artemether/lumefantrine as it is unknown whether the decrease in exposure of artemether or its active metabolite, dihydroartemisinin, could result in decreased antimalarial efficacy. No dose adjustment is needed for INTELENCE®. |
|
rifampin, rifapentine |
↓ etravirine | Rifampin and rifapentine are potent inducers of CYP450 enzymes. INTELENCE® should not be used with rifampin or rifapentine as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®. |
|
rifabutin |
↓ etravirine ↓ rifabutin ↓ 25- |
If INTELENCE® is NOT co-administered with a protease inhibitor/ritonavir, then rifabutin at a dose of 300 mg once daily is recommended. If INTELENCE® is co-administered with darunavir/ritonavir, lopinavir/ritonavir or saquinavir/ritonavir, then rifabutin should not be co-administered due to the potential for significant reductions in etravirine exposure. |
|
diazepam |
↑ diazepam | Concomitant use of INTELENCE® with diazepam may increase plasma concentrations of diazepam. A decrease in diazepam dose may be needed. |
|
dexamethasone (systemic) |
↓ etravirine | Systemic dexamethasone induces CYP3A and can decrease etravirine plasma concentrations. This may result in loss of therapeutic effect of INTELENCE®. Systemic dexamethasone should be used with caution or alternatives should be considered, particularly for long-term use. |
|
St. John's wort ( |
↓ etravirine | Concomitant use of INTELENCE® with products containing St. John's wort may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®. INTELENCE® and products containing St. John's wort should not be co-administered. |
|
telaprevir |
↔ etravirine ↓ telaprevir |
There are insufficient data to make a dosing recommendation for telaprevir when used with INTELENCE®. |
|
atorvastatin fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin |
↔ etravirine ↓ atorvastatin ↑ 2-OH-atorvastatin ↔ etravirine ↑ fluvastatin, ↓ lovastatin, ↑ pitavastatin, ↔ pravastatin, ↔ rosuvastatin, ↓ simvastatin |
The combination of INTELENCE® and atorvastatin can be given without dose adjustments, however, the dose of atorvastatin may need to be altered based on clinical response. No interaction between pravastatin, rosuvastatin and INTELENCE® is expected. Lovastatin and simvastatin are CYP3A substrates and co-administration with INTELENCE® may result in lower plasma concentrations of the HMG-CoA reductase inhibitor. Fluvastatin and pitavastatin are metabolized by CYP2C9 and co-administration with INTELENCE® may result in higher plasma concentrations of the HMG-CoA reductase inhibitor. Dose adjustments for these HMG-CoA reductase inhibitors may be necessary. |
|
cyclosporine, sirolimus, tacrolimus |
↓ immunosuppressant | INTELENCE® and systemic immunosuppressants should be co-administered with caution because plasma concentrations of cyclosporine, sirolimus, or tacrolimus may be affected. |
|
buprenorphine, buprenorphine/naloxone methadone |
↔ etravirine ↓ buprenorphine ↔ norbuprenorphine ↔ methadone |
INTELENCE® and buprenorphine (or buprenorphine/naloxone) can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as buprenorphine (or buprenorphine/naloxone) maintenance therapy may need to be adjusted in some patients. INTELENCE® and methadone can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as methadone maintenance therapy may need to be adjusted in some patients. |
|
sildenafil tadalafil, vardenafil |
↓ sildenafil ↓ N-desmethyl-sildenafil |
INTELENCE® and sildenafil can be co-administered without dose adjustments, however, the dose of sildenafil may need to be altered based on clinical effect. |
|
clopidogrel |
↓ clopidogrel (active) metabolite | Activation of clopidogrel to its active metabolite may be decreased when clopidogrel is co-administered with INTELENCE®. Alternatives to clopidogrel should be considered. |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
|
Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide |
|
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels. | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate |
|
Increased lamotrigine concentrations slightly more than 2 fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
| Coadministered Drug |
Dosing Schedule |
|
Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
|
Risperidone Dose Recommendation |
|
|
Coadministered Drug |
Risperidone |
AUC |
Cm
a
x
|
|
| Enzyme (CYP2D6) Inhibitors |
|
|
|
|
|
| Fluoxetine |
20 mg/day |
2 or 3 mg twice daily |
1.4 |
1.5 |
Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine |
10 mg/day |
4 mg/day |
1.3 |
- |
Re-evaluate dosing. |
|
|
20 mg/day |
4 mg/day |
1.6 |
- |
Do not exceed 8 mg/day |
|
|
40 mg/day |
4 mg/day |
1.8 |
- |
|
| Enzyme (CYP3A/ PgP inducers) |
|
|
|
|
|
| Carbamazepine |
573 ± 168 mg/day |
3 mg twice daily |
0.51 |
0.55 |
Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors |
|
|
|
|
|
| Ranitidine |
150 mg twice daily |
1 mg single dose |
1.2 |
1.4 |
Dose adjustment not needed |
| Cimetidine |
400 mg twice daily |
1 mg single dose |
1.1 |
1.3 |
Dose adjustment not needed |
| Erythromycin |
500 mg four times daily |
1 mg single dose |
1.1 |
0.94 |
Dose adjustment not needed |
| Other Drugs |
|
|
|
|
|
| Amitriptyline |
50 mg twice daily |
3 mg twice daily |
1.2 |
1.1 |
Dose adjustment not needed |
|
|
|
|
|
|---|---|
| Amphetamines, cocaine, other sympathomimetic agents | Additive hypertension, tachycardia, possibly cardiotoxicity |
| Atropine, scopolamine, antihistamines, other anticholinergic agents | Additive or super-additive tachycardia, drowsiness |
| Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants | Additive tachycardia, hypertension, drowsiness |
| Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants | Additive drowsiness and CNS depression |
| Disulfiram | A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge |
| Fluoxetine | A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days |
| Antipyrine, barbiturates | Decreased clearance of these agents, presumably via competitive inhibition of metabolism |
| Theophylline | Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco |
|
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|
| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
|
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|
|
| Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
|
|
|
| Amiodarone Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
|
|
|
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
|
|
|
|
|
|
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
| Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
|
|
|
|
|
|
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
|
|
|
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
|
|
|
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
|
|
|
| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone |
Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine |
Do not exceed 20 mg simvastatin daily |
| Grapefruit juice |
Avoid grapefruit juice |
| Drug | Effect | |
|---|---|---|
| Phenylephrine with prior administration of monoamine oxidase inhibitors (MAOI). |
Cardiac pressor response potentiated. May cause acute hypertensive crisis. |
|
| Phenylephrine with tricyclic anti-depressants. |
Pressor response increased. |
|
| Phenylephrine with ergot alkaloids. |
Excessive rise in blood pressure. |
|
| Phenylephrine with bronchodilator sympathomimetic agents and with epinephrine or other sympathomimetics. |
Tachycardia or other arrhythmias may occur. | |
| Phenylephrine with prior administration of propranolol or other β-adrenergic blockers. |
Cardiostimulating effects blocked. | |
| Phenylephrine with atropine sulfate. |
Reflex bradycardia blocked; pressor response enhanced. |
|
| Phenylephrine with prior administration of phentolamine or other α-adrenergic blockers. |
Pressor response decreased. | |
| Phenylephrine with diet preparations, such as amphetamines or phenylpropanolamine. |
Synergistic adrenergic response. |
| AED Coadministered |
AED Concentration |
Topiramate Concentration |
| Phenytoin | NC or 25% increasea | 48% decrease |
| Carbamazepine (CBZ) | NC | 40% decrease |
| CBZ epoxideb | NC | NE |
| Valproic acid | 11% decrease | 14% decrease |
| Phenobarbital | NC | NE |
| Primidone | NC | NE |
| Lamotrigine | NC at TPM doses up to 400 mg/day | 15% increase |
| Concomitant Drug Class: Drug Name | Effect | Clinical Comment |
|---|---|---|
|
|
||
| Protease inhibitor: atazanavir |
↓atazanavir concentration ↑ tenofovir concentration |
Coadministration of atazanavir with ATRIPLA is not recommended. Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA. |
| Protease inhibitor: fosamprenavir calcium |
↓ amprenavir concentration | Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and ATRIPLA with respect to safety and efficacy have not been established. Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when ATRIPLA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when ATRIPLA is administered with fosamprenavir plus ritonavir twice daily. |
| Protease inhibitor: indinavir |
↓ indinavir concentration | The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz. |
| Protease inhibitor: lopinavir/ritonavir |
↓ lopinavir concentration ↑ tenofovir concentration |
A dose increase of lopinavir/ritonavir to 600/150 mg (3 tablets) twice daily may be considered when used in combination with efavirenz in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). |
| Protease inhibitor: ritonavir |
↑ ritonavir concentration ↑ efavirenz concentration |
When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when ATRIPLA is used in combination with ritonavir. |
| Protease inhibitor: saquinavir |
↓ saquinavir concentration | Should not be used as sole protease inhibitor in combination with ATRIPLA. |
| CCR5 co-receptor antagonist: maraviroc |
↓ maraviroc concentration | Efavirenz decreases plasma concentrations of maraviroc. Refer to the full prescribing information for maraviroc for guidance on coadministration with ATRIPLA. |
| NRTI: didanosine |
↑ didanosine concentration | Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis and neuropathy. |
|
|
||
| Anticoagulant: warfarin |
↑ or ↓ warfarin concentration | Plasma concentrations and effects potentially increased or decreased by efavirenz. |
| Anticonvulsants: carbamazepine |
↓ carbamazepine concentration ↓ efavirenz concentration |
There are insufficient data to make a dose recommendation for ATRIPLA. Alternative anticonvulsant treatment should be used. |
| phenytoin phenobarbital |
↓ anticonvulsant concentration ↓ efavirenz concentration |
Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted. |
| Antidepressants: bupropion |
↓ buproprion concentration | The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded. |
| sertraline | ↓ sertraline concentration | Increases in sertraline dose should be guided by clinical response. |
| Antifungals: itraconazole |
↓ itraconazole concentration ↓ hydroxy-itraconazole concentration |
Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered. |
| ketoconazole | ↓ ketoconazole concentration | Drug interaction trials with ATRIPLA and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole. |
| posaconazole | ↓ posaconazole concentration | Avoid concomitant use unless the benefit outweighs the risks. |
| Anti-infective: clarithromycin |
↓ clarithromycin concentration ↑ 14-OH metabolite concentration |
Clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of ATRIPLA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with ATRIPLA. |
| Antimycobacterial: rifabutin |
↓ rifabutin concentration | Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week. |
| Antimycobacterial: rifampin |
↓ efavirenz concentration | If ATRIPLA is coadministered with rifampin to patients weighing 50 kg or more, an additional 200 mg/day of efavirenz is recommended. |
| Calcium channel blockers: diltiazem |
↓ diltiazem concentration ↓ desacetyl diltiazem concentration ↓ N-monodes-methyl diltiazem concentration |
Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of ATRIPLA is necessary when administered with diltiazem. |
| Others (e.g., felodipine, nicardipine, nifedipine, verapamil) |
↓ calcium channel blocker | No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker). |
| HMG-CoA reductase inhibitors: atorvastatin pravastatin simvastatin |
↓ atorvastatin concentration ↓ pravastatin concentration ↓ simvastatin concentration |
Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose. |
| Hormonal contraceptives: | ||
| Oral: ethinyl estradiol/norgestimate |
↓ active metabolites of norgestimate | A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed. |
| Implant: etonogestrel |
↓ etonogestrel | A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients. |
| Immunosuppressants: cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A |
↓ immuno-suppressant | Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by efavirenz. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with ATRIPLA. |
| Narcotic analgesic: methadone |
↓ methadone concentration | Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms. |
| albuterol, systemic and inhaled | diltiazem | medroxyprogesterone | roxithromycin |
| dirithromycin | methylprednisolone | Sorbitol (purgative doses do not inhibit theophylline absorption) |
|
| amoxicillin | enflurane | metronidazole | |
| ampicillin, with or without sulbactam | famotidine | metoprolol | |
| felodipine | nadolol | ||
| finasteride | nifedipine | ||
| atenolol | hydrocortisone | nizatidine | sucralfate |
| azithromycin | isoflurane | norfloxacin | terbutaline, systemic |
| caffeine, dietary ingestion | isoniazid | ofloxacin | terfenadine |
| isradipine | omeprazole | tetracycline | |
| cefaclor | influenza vaccine | prednisone, prednisolone |
tocainide |
| co-trimoxazole (trimethoprim and sulfamethoxazole) | ketoconazole | ||
| lomefloxacin | ranitidine | ||
| mebendazole | rifabutin | ||
| * Refer to PRECAUTIONS, Drug Interactions for information regarding table. | |||
|
|
|
|
|
|
||
| Atazanavir/Ritonavir* | ↓ Atazanavir ↑ Nevirapine |
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures. |
| Fosamprenavir* Fosamprenavir/Ritonavir* |
↓ Amprenavir ↑ Nevirapine ↓ Amprenavir ↑ Nevirapine |
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied. |
| Indinavir* | ↓ Indinavir | The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established. |
| Lopinavir/Ritonavir* | ↓Lopinavir | Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. |
| Nelfinavir* | ↓Nelfinavir M8 Metabolite ↓Nelfinavir Cmin |
The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established. |
| Saquinavir/ritonavir | The interaction between Nevirapine and saquinavir/ritonavir has not been evaluated | The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established. |
|
|
||
| Efavirenz* Delavirdine Etravirine Rilpivirine |
↓ Efavirenz | The appropriate doses of these combinations with respect to safety and efficacy have not been established. Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial. |
|
|
||
|
Methadone* |
↓ Methadone | Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. |
|
|
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
|
Clarithromycin* Rifabutin* Rifampin* |
↓ Clarithromycin ↑ 14-OH clarithromycin ↑ Rifabutin ↓ Nevirapine |
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered. Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead. |
|
Carbamazepine, clonazepam, ethosuximide |
Plasma concentrations of nevirapine and the anticonvulsant may be decreased. | Use with caution and monitor virologic response and levels of anticonvulsants. |
|
Fluconazole* Ketoconazole* Itraconazole |
↑Nevirapine ↓ Ketoconazole ↓ Itraconazole |
Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events. Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug. |
|
Warfarin |
Plasma concentrations may be increased. | Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended. |
|
|
Plasma concentrations may be decreased. | Appropriate doses for these combinations have not been established. |
|
|
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
|
|
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
|
|
Plasma concentrations may be decreased. | Appropriate doses for these combinations have not been established. |
|
|
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
|
|
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
|
Ethinyl estradiol and Norethindrone* |
↓ Ethinyl estradiol ↓ Norethindrone |
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception |
| * The interaction between Nevirapine and the drug was evaluated in a clinical study. All other drug interactions shown are predicted. | ||
| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
|
|
|
|
|
|
|
|
| ciprofloxacin | melphalan | amphotericin B | azapropazon | cimetidine | tacrolimus | fibric acid derivatives (e.g., bezafibrate, fenofibrate) |
| gentamicin | ketoconazole | colchicine | ranitidine | methotrexate | ||
| tobramycin | diclofenac | |||||
| trimethoprim with sulfamethoxazole |
naproxen | |||||
| vancomycin | sulindac |
|
|
|
|
|
|
| diltiazem | fluconazole | azithromycin | methylprednisolone | allopurinol |
| nicardipine | itraconazole | clarithromycin | amiodarone | |
| verapamil | ketoconazole | erythromycin | bromocriptine | |
| voriconazole | quinupristin/ dalfopristin |
colchicine | ||
| danazol | ||||
| imatinib | ||||
| metoclopramide | ||||
| nefazodone | ||||
| oral contraceptives |
|
|
|
|
|
| nafcillin | carbamazepine | bosentan | St. John’s Wort |
| rifampin | oxcarbazepine | octreotide | |
| phenobarbital | orlistat | ||
| phenytoin | sulfinpyrazone | ||
| terbinafine | |||
| ticlopidine | |||
| Coadministered Drug | Dosing Schedule | Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio |
Risperidone Dose Recommendation | ||
| Coadministered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6) Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 mg twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/ PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient's usual dose |
| Enzyme (CYP3A) Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
|
|
||
|
|
Nevirapine or Concomitant Drug |
|
|
|
||
| Atazanavir/Ritonavir* | ↓ Atazanavir ↑ Nevirapine |
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures. |
| Fosamprenavir* Fosamprenavir/Ritonavir* |
↓ Amprenavir ↑ Nevirapine ↓ Amprenavir ↑ Nevirapine |
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied. |
| Indinavir* | ↓ Indinavir | The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established. |
| Lopinavir/Ritonavir* | ↓Lopinavir | Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. |
| Nelfinavir* | ↓Nelfinavir M8 Metabolite ↓Nelfinavir Cmin |
The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established. |
| Saquinavir/ritonavir | The interaction between VIRAMUNE and saquinavir/ritonavir has not been evaluated | The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established. |
|
|
||
| Efavirenz* Delavirdine Etravirine Rilpivirine |
↓ Efavirenz | The appropriate doses of these combinations with respect to safety and efficacy have not been established. Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial. |
|
|
||
|
Methadone* |
↓ Methadone | Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. |
|
Amiodarone, disopyramide, lidocaine |
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
|
Clarithromycin* Rifabutin* Rifampin* |
↓ Clarithromycin ↑ 14-OH clarithromycin ↑ Rifabutin ↓ Nevirapine |
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead. |
|
Carbamazepine, clonazepam, ethosuximide |
Plasma concentrations of nevirapine and the anticonvulsant may be decreased. | Use with caution and monitor virologic response and levels of anticonvulsants. |
|
Fluconazole* Ketoconazole* Itraconazole |
↑Nevirapine ↓ Ketoconazole ↓ Itraconazole |
Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events. Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug. |
|
Warfarin |
Plasma concentrations may be increased. |
Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended. |
|
Diltiazem, nifedipine, verapamil |
Plasma concentrations may be decreased. |
Appropriate doses for these combinations have not been established. |
|
Cyclophosphamide |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
Ergotamine |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
Cyclosporine, tacrolimus, sirolimus |
Plasma concentrations may be decreased. |
Appropriate doses for these combinations have not been established. |
|
Cisapride |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
Fentanyl |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
Ethinyl estradiol and Norethindrone* |
↓ Ethinyl estradiol ↓ Norethindrone |
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended. |
| Concomitant Drug Class or Food | Noted or anticipated Outcome | Clinical Comment |
|---|---|---|
|
atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin |
Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality) | Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy. |
|
fibrates, gemfibrozil |
||
|
digoxin |
P-gp substrate; rhabdomyolysis has been reported |
| * Change relative to reference |
|||||
| Coadministered Drug |
Dosing Schedule |
Effect on Active Moiety (Risperidone + 9-Hydroxy- Risperidone Ratio*) |
Risperidone Dose Recommendation |
||
| Coadministered Drug |
Risperidone |
AUC |
Cmax
|
||
| Enzyme (CYP2D6) Inhibitors |
|
|
|
|
|
| Fluoxetine |
20 mg/day |
2 or 3 mg twice daily |
1.4 |
1.5 |
Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine |
10 mg/day |
4 mg/day |
1.3 |
- |
Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day |
4 mg/day |
1.6 |
- |
||
| 40 mg/day |
4 mg/day |
1.8 |
- |
||
| Enzyme (CYP3A/ PgP inducers) Inducers |
|||||
| Carbamazepine |
573 ± 168 mg/day |
3 mg twice daily |
0.51 |
0.55 |
Titrate dose upwards. Do not exceed twice the patients usual dose |
| Enzyme (CYP3A) Inhibitors |
|||||
| Ranitidine |
150 mg twice daily |
1 mg single dose |
1.2 |
1.4 |
Dose adjustment not needed |
| Cimetidine |
400 mg twice daily |
1 mg single dose |
1.1 |
1.3 |
Dose adjustment not needed |
| Erythromycin |
500 mg four times daily |
1 mg single dose |
1.1 |
0.94 |
Dose adjustment not needed |
| Other Drugs |
|||||
| Amitriptyline |
50 mg twice daily |
3 mg twice daily |
1.2 |
1.1 |
Dose adjustment not needed |
| * The interaction between nevirapine and the drug was evaluated in a clinical study. All other drug interactions shown are predicted. | ||
|
|
|
|
|
|
||
| Atazanavir/Ritonavir* |
↓ Atazanavir ↑ Nevirapine |
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures. |
| Fosamprenavir* Fosamprenavir/Ritonavir* |
↓Amprenavir ↑Nevirapine ↓Amprenavir ↑Nevirapine |
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied. |
| Indinavir* |
↓ Indinavir |
The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established. |
| Lopinavir/Ritonavir* |
↓ Lopinavir |
Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. |
| Nelfinavir* |
↓Nelfinavir M8 Metabolite ↓Nelfinavir Cmin |
The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established. |
| Saquinavir/ritonavir |
The interaction between nevirapine and saquinavir/ritonavir has not been evaluated |
The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established. |
|
|
||
| Efavirenz* Delavirdine Etravirine Rilpivirine |
↓Efavirenz |
The appropriate doses of these combinations with respect to safety and efficacy have not been established. Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial. |
|
|
||
|
Methadone* |
↓Methadone |
Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. |
|
Amiodarone, disopyramide, lidocaine |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
Clarithromycin* Rifabutin* Rifampin* |
↓Clarithromycin ↑14-OH clarithromycin ↑Rifabutin ↓ Nevirapine |
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead. |
|
Carbamazepine, clonazepam, ethosuximide |
Plasma concentrations of nevirapine and the anticonvulsant may be decreased. |
Use with caution and monitor virologic response and levels of anticonvulsants. |
|
Fluconazole* Ketoconazole* Itraconazole |
↑Nevirapine ↓ Ketoconazole ↓ Itraconazole |
Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events. Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug. |
|
Warfarin |
Plasma concentrations may be increased. |
Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended. |
|
Diltiazem, nifedipine, verapamil |
Plasma concentrations may be decreased. |
Appropriate doses for these combinations have not been established. |
|
Cyclophosphamide |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
Ergotamine |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
|
Plasma concentrations may be decreased. |
Appropriate doses for these combinations have not been established. |
|
Cisapride |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
Fentanyl |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
Ethinyl estradiol and Norethindrone* |
↓ Ethinyl estradiol ↓ Norethindrone |
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended. |
| Concomitant Drug |
Effect on Concentration of Lamotrigine or Concomitant Drug |
Clinical Comment |
| Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine ↓ levonorgestrel |
Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%. |
|
Carbamazepine (CBZ) and CBZ epoxide |
↓ lamotrigine ? CBZ epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40% May increase CBZ epoxide levels |
| Phenobarbital/Primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40%. |
| Valproate |
↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
|
|
|
|
|
|
||
| Dopamine / Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day). | |
|
|
||
|
|
||
| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | |
|
|
||
| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | |
|
|
||
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | |
|
|
||
|
|
|
|
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | |
|
|
||
|
|
||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | |
|
|
||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | |
|
|
||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms. | |
|
|
|||||
|
|
|||||
| Dopamine / Dopamine Agonists | Glucocorticoids | Octreotide | |||
|
|
|||||
|
|
|||||
|
|
|||||
|
|
|||||
| Aminoglutethimide Amiodarone |
Iodide (including iodine-containing Radiographic contrast agents) Lithium |
Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
|||
|
|
|||||
|
|
|||||
|
|
|||||
| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
|||||
|
|
|||||
|
|
|||||
|
|
|||||
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone |
Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate |
Cation Exchange Resins - Kayexalate Ferrous Sulfate Sucralfate |
|||
|
|
|||||
|
|
|||||
|
|
|||||
| Clofibrate Estrogen-containing oral contraceptives |
Estrogens (oral) Heroin / Methadone 5-Fluorouracil |
Mitotane Tamoxifen |
|||
|
|
|||||
| Androgens / Anabolic Steroids | Glucocorticoids | ||||
| Asparaginase | Slow Release Nicotinic Acid | ||||
|
|
|||||
|
|
|||||
| Furosemide ( > 80 mg IV) Heparin Hydantoins |
Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
||||
|
|
|||||
|
|
|||||
|
|
|||||
|
|
|||||
| Carbamazepine | Hydantoins | Phenobarbital | Rifampin | ||
|
|
|||||
|
|
|||||
|
|
|||||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) |
Glucocorticoids - (e.g., Dexamethasone ≥4 mg/day) Propylthiouracil (PTU) |
||||
|
|
|||||
|
|
|||||
|
|
|||||
| Anticoagulants (oral) | |||||
| - Coumarin Derivatives | - Indandione Derivatives | ||||
|
|
|||||
|
|
|||||
| Antidepressants | |||||
| - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) |
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
||||
|
|
|||||
|
|
|||||
| Antidiabetic Agents - Biguanides |
- Meglitinides - Thiazolidinediones |
- Sulfonylureas - Insulin |
|||
|
|
|||||
|
|
|||||
| Cardiac Glycosides | |||||
|
|
|||||
|
|
|||||
| Cytokines | - Interferon-α | - Interleukin-2 | |||
|
|
|||||
|
|
|||||
| Growth Hormones | - Somatrem | - Somatropin | |||
|
|
|||||
|
|
|||||
| Ketamine | |||||
|
|
|||||
|
|
|||||
| Methylxanthine Bronchodilators - (e.g., Theophylline) | |||||
|
|
|||||
|
|
|||||
| Radiographic Agents | |||||
|
|
|||||
|
|
|||||
| Sympathomimetics | |||||
|
|
|||||
|
|
|||||
| Chloral Hydrate Diazepam Ethionamide Lovastatin |
Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium |
Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
|||
|
|
|||||
| Coadministered Drug |
Dosing Schedule |
|
Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
|
Risperidone Dose Recommendation |
|
|
Coadministered Drug |
Risperidone |
AUC |
Cm
a
x
|
|
| Enzyme (CYP2D6) Inhibitors |
|
|
|
|
|
| Fluoxetine |
20 mg/day |
2 or 3 mg twice daily |
1.4 |
1.5 |
Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine |
10 mg/day |
4 mg/day |
1.3 |
- |
Re-evaluate dosing. |
|
|
20 mg/day |
4 mg/day |
1.6 |
- |
Do not exceed 8 mg/day |
|
|
40 mg/day |
4 mg/day |
1.8 |
- |
|
| Enzyme (CYP3A/ PgP inducers) |
|
|
|
|
|
| Carbamazepine |
573 ± 168 mg/day |
3 mg twice daily |
0.51 |
0.55 |
Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors |
|
|
|
|
|
| Ranitidine |
150 mg twice daily |
1 mg single dose |
1.2 |
1.4 |
Dose adjustment not needed |
| Cimetidine |
400 mg twice daily |
1 mg single dose |
1.1 |
1.3 |
Dose adjustment not needed |
| Erythromycin |
500 mg four times daily |
1 mg single dose |
1.1 |
0.94 |
Dose adjustment not needed |
| Other Drugs |
|
|
|
|
|
| Amitriptyline |
50 mg twice daily |
3 mg twice daily |
1.2 |
1.1 |
Dose adjustment not needed |
|
|
|
|
|
| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid grapefruit juice |
|
|
|
|
|
|
||
| Atazanavir/Ritonavir* |
↓ Atazanavir ↑ Nevirapine |
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures. |
| Fosamprenavir* |
↓ Amprenavir ↑ Nevirapine |
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. |
| Fosamprenavir/Ritonavir* |
↓ Amprenavir ↑ Nevirapine |
No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied. |
| Indinavir* |
↓ Indinavir |
The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established. |
| Lopinavir/Ritonavir* |
↓Lopinavir |
Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. |
| Nelfinavir* |
↓Nelfinavir M8 Metabolite ↓Nelfinavir Cmin |
The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy, has not been established. |
| Saquinavir/Ritonavir |
The interaction between nevirapine and saquinavir/ritonavir has not been evaluated. |
The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established. |
|
|
||
| Efavirenz* |
↓ Efavirenz |
The appropriate doses of these combinations with respect to safety and efficacy have not been established. |
| Delavirdine Etravirine Rilpivirine |
|
Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial. |
|
|
||
|
Methadone* |
↓ Methadone |
Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. |
|
Amiodarone, disopyramide, lidocaine |
Plasma concentrations may be decreased. |
Appropriate doses for this combination have not been established. |
|
Clarithromycin* |
↓ Clarithromycin ↑ 14-OH clarithromycin |
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered. |
| Rifabutin* |
↑Rifabutin |
Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. |
| Rifampin* |
↓ Nevirapine |
Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead. |
|
|
Plasma concentrations of nevirapine and the anticonvulsant may be decreased. |
Use with caution and monitor virologic response and levels of anticonvulsants. |
|
Fluconazole* |
↑ Nevirapine |
Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events. |
| Ketoconazole* |
↓ Ketoconazole |
Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. |
| Itraconazole |
↓ Itraconazole |
Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug. |
|
Warfarin |
Plasma concentrations may be increased. |
Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended. |
|
Diltiazem, nifedipine, verapamil |
Plasma concentrations may be decreased. |
Appropriate doses for these combinations have not been established. |
|
|
Plasma concentrations may be decreased. |
Appropriate doses for these combinations have not been established. |
|
|
Plasma concentrations may be decreased. |
Appropriate doses for these combinations have not been established. |
|
|
Plasma concentrations may be decreased. |
Appropriate doses for these combinations have not been established. |
|
|
Plasma concentrations may be decreased. |
Appropriate doses for these combinations have not been established. |
|
|
Plasma concentrations may be decreased. |
Appropriate doses for these combinations have not been established. |
|
|
↓ Ethinyl estradiol ↓ Norethindrone |
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended. |
| * The interaction between nevirapine and the drug was evaluated in a clinical study. All other drug interactions shown are predicted. |
||
|
|
|
||
|
|
|||
| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
|
|
|||
|
|
|||
| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
|
|
|||
|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
| |
|||
|
|
|
||
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
||
|
|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
| |
|||
| |
|||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
|
|
|||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
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|||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
| AED Coadministered |
AED Concentration |
Topiramate Concentration |
| Phenytoin | NC or 25% increase |
48% decrease |
| Carbamazepine (CBZ) | NC | 40% decrease |
| CBZ epoxide |
NC | NE |
| Valproic acid | 11% decrease | 14% decrease |
| Phenobarbital | NC | NE |
| Primidone | NC | NE |
| Lamotrigine | NC at TPM doses up to 400 mg/day | 15% increase |
| NC = Less than 10% change in plasma concentration AED = Antiepileptic drug NE = Not Evaluated TPM = Topiramate |
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|
| ganciclovir | ↑ didanosine concentration | If there is no suitable alternative to ganciclovir, then use in combination with didanosine delayed-release with caution. Monitor for didanosine-associated toxicity. |
| methadone | ↓ didanosine concentration | If coadministration of methadone and didanosine is necessary, the recommended formulation of dianosine is didanosine delayed-release. Patients should be closely monitored for adequate clinical response when didanosine delayed-release is coadministered with methadone, including monitoring for changes in HIV RNA viral load. Do not coadminister methadone with didanosine pediatric powder due to significant decreases in didanosine concentrations. |
| nelfinavir | No interaction one hour after didanosine | Administer nelfinavir one hour after didanosine delayed-release. |
| tenofovir disoproxil fumarate | ↑ didanosine concentration | A dose reduction of didanosine delayed-release capsules to the following dosage once daily taken together with tenofovir disoproxil fumarate and a light meal (400 kcalories or less and 20% fat or less) or in the fasted state is recommended. • 250 mg (adults weighing at least 60 kg with creatinine clearance of at least 60 mL/min) • 200 mg (adults weighing less than 60 kg with creatinine clearance of at least 60 mL/min Patients should be monitored for didanosine-associated toxicities and clinical response. |
| ↑ indicates increase ↓ indicates decrease |
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| Drugs that may cause pancreatic toxicity | ↑ risk of pancreatitis | Use only with extreme caution. |
| Neurotoxic drugs | ↑ risk of neuropathy | Use with caution. |
| ↑ Indicates increase | ||
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|
| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid grapefruit juice |
|
|
|
| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid grapefruit juice |
| |
|
| |
Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| |
Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) | Do not exceed 40 mg atorvastatin daily |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
|
Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide |
|
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels. | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate |
|
Increased lamotrigine concentrations slightly more than 2 fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
|
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|
|
| Atazanavir/Ritonavir | ↓ Atazanavir ↑ Nevirapine |
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure. |
| Clarithromycin | ↓ Clarithromycin ↑ 14-OH clarithromycin |
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against |
| Efavirenz | ↓ Efavirenz | There has been no determination of appropriate doses for the safe and effective use of this combination [ |
| Ethinyl estradiol and Norethindrone | ↓ Ethinyl estradiol ↓ Norethindrone |
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended. |
| Fluconazole | ↑ Nevirapine | Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events. |
| Fosamprenavir | ↓ Amprenavir ↑ Nevirapine |
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. |
| Fosamprenavir/Ritonavir | ↓ Amprenavir ↑ Nevirapine |
No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. |
| Indinavir | ↓ Indinavir | Appropriate doses for this combination are not established, but an increase in the dosage of indinavir may be required. |
| Ketoconazole | ↓ Ketoconazole | Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. |
| Lopinavir/Ritonavir | ↓ Lopinavir |
|
| Methadone | ↓ Methadone | Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. |
| Nelfinavir | ↓ Nelfinavir M8 Metabolite ↓ Nelfinavir Cmin |
The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established. |
| Rifabutin | ↑Rifabutin | Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. |
| Rifampin | ↓ Nevirapine | Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead. |
| Saquinavir/ritonavir | The interaction between Nevirapine and saquinavir/ritonavir has not been evaluated | The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established. |
|
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|
| Antiarrhythmics | Amiodarone, disopyramide, lidocaine | Plasma concentrations may be decreased. |
| Anticonvulsants | Carbamazepine, clonazepam, ethosuximide | Plasma concentrations may be decreased. |
| Antifungals | Itraconazole | Plasma concentrations of some azole antifungals may be decreased. Nevirapine and itraconazole should not be administered concomitantly due to a potential decrease in itraconazole plasma concentrations. |
| Calcium channel blockers | Diltiazem, nifedipine, verapamil | Plasma concentrations may be decreased. |
| Cancer chemotherapy | Cyclophosphamide | Plasma concentrations may be decreased. |
| Ergot alkaloids | Ergotamine | Plasma concentrations may be decreased. |
| Immunosuppressants | Cyclosporin, tacrolimus, sirolimus | Plasma concentrations may be decreased. |
| Motility agents | Cisapride | Plasma concentrations may be decreased. |
| Opiate agonists | Fentanyl | Plasma concentrations may be decreased. |
| Antithrombotics | Warfarin | Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended. |
|
|
Nevirapine or Concomitant Drug |
|
| Atazanavir/Ritonavir | ↓ Atazanavir ↑ Nevirapine |
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure. |
| Clarithromycin | ↓ Clarithromycin ↑ 14-OH clarithromycin |
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against |
| Efavirenz | ↓ Efavirenz | There has been no determination of appropriate doses for the safe and effective use of this combination [ |
| Ethinyl estradiol and Norethindrone | ↓ Ethinyl estradiol ↓ Norethindrone |
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended. |
| Fluconazole | ↑Nevirapine | Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events. |
| Fosamprenavir | ↓ Amprenavir ↑ Nevirapine |
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. |
| Fosamprenavir/Ritonavir | ↓ Amprenavir ↑ Nevirapine |
No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. |
| Indinavir | ↓ Indinavir | Appropriate doses for this combination are not established, but an increase in the dosage of indinavir may be required. |
| Ketoconazole | ↓ Ketoconazole | Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. |
| Lopinavir/Ritonavir | ↓Lopinavir | A dose increase of lopinavir/ritonavir tablets to 500/125 mg twice-daily is recommended when used in combination with nevirapine. A dose increase of lopinavir/ritonavir oral solution to 533/133 mg twice daily with food is recommended in combination with nevirapine. In children 6 months to 12 years of age receiving lopinavir/ritonavir solution, consideration should be given to increasing the dose of lopinavir/ritonavir to 13/3.25 mg/kg for those 7 to <15 kg; 11/2.75 mg/kg for those 15 to 45 kg; up to a maximum dose of 533/133 mg twice daily. Refer to the lopinavir/ritonavir package insert for complete pediatric dosing instructions when lopinavir/ritonavir tablets are used in combination with nevirapine. |
| Methadone | ↓ Methadone | Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. |
| Nelfinavir | ↓Nelfinavir M8 Metabolite ↓Nelfinavir Cmin |
The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established. |
| Rifabutin | ↑Rifabutin | Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. |
| Rifampin | ↓ Nevirapine | Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead. |
| Saquinavir/Ritonavir | The interaction between nevirapine and saquinavir/ritonavir has not been evaluated | The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established. |
|
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||
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|
|
| Antiarrhythmics | Amiodarone, disopyramide, lidocaine | Plasma concentrations may be decreased. |
| Anticonvulsants | Carbamazepine, clonazepam, ethosuximide | Plasma concentrations may be decreased. |
| Antifungals | Itraconazole | Plasma concentrations of some azole antifungals may be decreased. Nevirapine and itraconazole should not be administered concomitantly due to a potential decrease in itraconazole plasma concentrations. |
| Calcium channel blockers | Diltiazem, nifedipine, verapamil | Plasma concentrations may be decreased. |
| Cancer chemotherapy | Cyclophosphamide | Plasma concentrations may be decreased. |
| Ergot alkaloids | Ergotamine | Plasma concentrations may be decreased. |
| Immunosuppressants | Cyclosporin, tacrolimus, sirolimus | Plasma concentrations may be decreased. |
| Motility agents | Cisapride | Plasma concentrations may be decreased. |
| Opiate agonists | Fentanyl | Plasma concentrations may be decreased. |
| Antithrombotics | Warfarin | Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended. |
| Enzyme | Inhibitors | Inducers |
|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
| Drug Class | Specific Drugs |
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
|
|
|
| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, fibrates |
Avoid VYTORIN |
| Cyclosporine, danazol | Do not exceed 10/10 mg VYTORIN daily |
| Amiodarone, verapamil | Do not exceed 10/20 mg VYTORIN daily |
| Diltiazem | Do not exceed 10/40 mg VYTORIN daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
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Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
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Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
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|
Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function. |
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Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4 . Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
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Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
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Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
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|
- Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
|
- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
|
- Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
|
- Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
|
- Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
|
- (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
|
Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
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| Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Amiodarone, verapamil, diltiazem | Do not exceed 10 mg simvastatin daily |
| Amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
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| Phenytoin |
NC or 25% increasea
|
48% decrease |
| Carbamazepine (CBZ) |
NC |
40% decrease |
| CBZ epoxideb
|
NC |
NE |
| Valproic acid |
11% decrease |
14% decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NC at TPM doses up to 400 mg/day |
13% decrease |
| AED Coadministered | Dose of AED (mg/day) |
Oxcarbazepine Dose (mg/day) |
Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval) | Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval) |
|---|---|---|---|---|
| Carbamazepine | 400-2000 | 900 | nc |
40% decrease [CI:17% decrease, 57% decrease] |
| Phenobarbital | 100-150 | 600-1800 | 14% increase [CI: 2% increase, 24% increase] |
25% decrease [CI:12% decrease, 51% decrease] |
| Phenytoin | 250-500 | 600-1800 >1200-2400 |
nc up to 40% increase [CI: 12% increase, 60% increase] |
30% decrease [CI: 3% decrease, 48% decrease] |
| Valproic acid | 400-2800 | 600-1800 | nc |
18% decrease [CI:13% decrease, 40% decrease] |
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Non-nucleoside Reverse Transcriptase
Inhibitors: efavirenz*, nevirapine* |
↓ lopinavir |
KALETRA dose increase is recommended in all patients Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz. KALETRA should not be administered once daily in combination with efavirenz or nevirapine |
|
Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine |
↑ lopinavir | Appropriate doses of the combination with respect to safety and efficacy have not been established. |
|
Nucleoside Reverse Transcriptase Inhibitor: didanosine |
|
KALETRA tablets can be administered simultaneously with didanosine without
food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food). |
|
Nucleoside Reverse Transcriptase Inhibitor: tenofovir |
↑ tenofovir | KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir. |
|
Nucleoside Reverse Transcriptase Inhibitor: abacavir zidovudine |
↓ abacavir ↓ zidovudine |
KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown. |
|
HIV-1 Protease Inhibitor: amprenavir* |
↑ amprenavir ↓ lopinavir |
KALETRA should not be administered once daily in combination with amprenavir
|
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HIV-1 Protease Inhibitor: fosamprenavir/ritonavir |
↓ amprenavir ↓ lopinavir |
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established. |
|
HIV-1 Protease Inhibitor: indinavir* |
↑ indinavir |
Decrease indinavir dose to 600 mg twice daily, when co-administered with
KALETRA 400/100 mg twice daily |
|
HIV-1 Protease Inhibitor: nelfinavir* |
↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir |
KALETRA should not be administered once daily in combination with
nelfinavir |
|
HIV-1 Protease Inhibitor: ritonavir* |
↑ lopinavir | Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established. |
|
HIV-1 Protease Inhibitor: saquinavir* |
↑ saquinavir |
The saquinavir dose is 1000 mg twice daily, when co-administered with
KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir. |
|
HIV-1 Protease Inhibitor: tipranavir |
↓ lopinavir AUC and Cmin | KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily). |
| HIV CCR5 – antagonist: maraviroc | ↑ maraviroc | Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry® (maraviroc). |
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Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), and quinidine |
↑ antiarrhythmics | Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA. |
|
Anticancer Agents: vincristine, vinblastine, dasatinib, nilotinib |
↑ anticancer agents |
Concentrations of these drugs may be increased when co-administered with
KALETRA resulting in the potential for increased adverse events usually
associated with these anticancer agents. For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions. |
|
Anticoagulant: warfarin |
|
Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored. |
|
Anticonvulsants: carbamazepine, phenobarbital, phenytoin |
↓ lopinavir ↓ phenytoin |
KALETRA may be less effective due to decreased lopinavir plasma
concentrations in patients taking these agents concomitantly and should be used
with caution. KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA. |
|
Antidepressant: bupropion |
↓ bupropion ↓ active metabolite, hydroxybupropion |
Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion. |
|
Antidepressant: trazodone |
↑ trazodone | Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered. |
|
Anti-infective: clarithromycin |
↑ clarithromycin |
For patients with renal impairment, the following dosage adjustments should
be considered:
No dose adjustment for patients with normal renal function is necessary. |
|
Antifungals: ketoconazole*, itraconazole, voriconazole |
↑ ketoconazole ↑ itraconazole ↓ voriconazole |
High doses of ketoconazole (less then 200 mg/day) or itraconazole
(less then 200 mg/day) are not recommended. Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients. |
|
Anti-gout: colchicine |
↑ colchicine |
Patients with renal or hepatic impairment should not be given colchicine
with KALETRA.
0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). |
|
Antimycobacterial: rifabutin* |
↑ rifabutin and rifabutin metabolite | Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary. |
|
Antimycobacterial: rifampin |
↓ lopinavir |
May lead to loss of virologic response and possible resistance to KALETRA or
to the class of protease inhibitors or other co-administered antiretroviral
agents. A study evaluated combination of rifampin 600 mg once daily, with
KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice
daily. Pharmacokinetic and safety results from this study do not allow for a
dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in
ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based
on the study design, it is not possible to determine whether the frequency or
magnitude of the ALT/AST elevations observed is higher than what would be seen
with rifampin alone |
|
Antiparasitic: atovaquone |
↓ atovaquone | Clinical significance is unknown; however, increase in atovaquone doses may be needed. |
| Benzodiazepines: parenterally administered midazolam | ↑ midazolam |
Midazolam is extensively metabolized by CYP3A4. Increases in the
concentration of midazolam are expected to be significantly higher with oral
than parenteral administration. Therefore, KALETRA should not be given with
orally administered midazolam |
|
Calcium Channel Blockers, dihydropyridine: e.g., felodipine, nifedipine, nicardipine |
↑ dihydropyridine calcium channel blockers | Caution is warranted and clinical monitoring of patients is recommended. |
|
Contraceptive: ethinyl estradiol* |
↓ ethinyl estradiol | Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended. |
|
Corticosteroid: dexamethasone |
↓ lopinavir |
Use with caution. KALETRA may be less effective due to decreased lopinavir
plasma concentrations in patients taking these agents
concomitantly. |
| disulfiram/metronidazole |
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Endothelin receptor antagonists: bosentan |
↑ bosentan |
In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. |
|
HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin |
↑ atorvastatin ↑ rosuvastatin |
Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with KALETRA. |
|
Immunosuppressants: cyclosporine, tacrolimus, rapamycin |
↑ immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA. |
|
Inhaled Steroid: fluticasone |
↑ fluticasone | Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect. |
|
Long-acting beta-adrenoceptor agonist: salmeterol |
↑ salmeterol | Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
|
Narcotic Analgesic: methadone* fentanyl |
↓ methadone ↑ fentanyl |
Dosage of methadone may need to be increased when co-administered with
KALETRA. Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA. |
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PDE5 inhibitors: sildenafil, tadalafil, vardenafil |
↑ sildenafil ↑ tadalafil ↑ vardenafil |
Particular caution should be used when prescribing sildenafil, tadalafil, or
vardenafil in patients receiving KALETRA. Co-administration of KALETRA with
these drugs is expected to substantially increase their concentrations and may
result in an increase in PDE5 inhibitor associated adverse reactions including
hypotension, syncope, visual changes and prolonged erection.
Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA The following dose adjustments are recommended for use of tadalafil (Adcirca®) with KALETRA: In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: It is recommended not to exceed the following doses:
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| AED Co-administered |
AED Concentration |
Topiramate Concentration |
| Phenytoin |
NC or 25% increasea
|
48% decrease |
| Carbamazepine (CBZ) |
NC |
40% decrease |
| CBZ epoxideb
|
NC |
NE |
| Valproic acid |
11% decrease |
14% decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NC at TPM doses up to 400 mg/day |
13% decrease |
| Enzyme | Inhibitors | Inducers |
|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
| Drug Class | Specific Drugs |
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
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| Amiodarone Iodide (including iodine- containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
| albuterol, | famotidine | nizatidine |
| systemic and inhaled | felodipine | norfloxacin |
| amoxicillin | finasteride | ofloxacin |
| ampicillin, | hydrocortisone | omeprazole |
| with or without | isoflurane | prednisone, prednisolone |
| sulbactam | isoniazid | ranitidine |
| atenolol | isradipine | rifabutin |
| azithromycin | influenza vaccine | roxithromycin |
| caffeine, | ketoconazole | sorbitol |
| dietary ingestion | lomefloxacin | (purgative doses do not |
| cefaclor | mebendazole | inhibit theophylline |
| co-trimoxazole | medroxyprogesterone | absorption) |
| (trimethoprim and | methylprednisolone | sucralfate |
| sulfamethoxazole) | metronidazole | terbutaline, systemic |
| diltiazem | metoprolol | terfenadine |
| dirithromycin | nadolol | tetracycline |
| enflurane | nifedipine | tocainide |
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| Concomitant Drug Class: Drug Name |
Effect on Concentration of Darunavir or Concomitant Drug | Clinical Comment |
|---|---|---|
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| didanosine | ↔ darunavir ↔ didanosine |
Didanosine should be administered one hour before or two hours after PREZISTA/ritonavir (which are administered with food). |
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| indinavir (The reference regimen for indinavir was indinavir/ritonavir 800/100 mg twice daily.) |
↑ darunavir ↑ indinavir |
The appropriate dose of indinavir in combination with PREZISTA/ritonavir has not been established. |
| lopinavir/ritonavir | ↓ darunavir ↔ lopinavir |
Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer lopinavir/ritonavir and PREZISTA, with or without ritonavir. |
| saquinavir | ↓ darunavir ↔ saquinavir |
Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer saquinavir and PREZISTA, with or without ritonavir. |
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| maraviroc | ↑ maraviroc | Maraviroc concentrations are increased when co-administered with PREZISTA/ritonavir. When used in combination with PREZISTA/ritonavir, the dose of maraviroc should be 150 mg twice daily. |
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|
bepridil, lidocaine (systemic), quinidine, amiodarone, flecainide, propafenone |
↑ antiarrhythmics | Concentrations of these drugs may be increased when co-administered with PREZISTA/ritonavir. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when co-administered with PREZISTA/ritonavir. |
| digoxin | ↑ digoxin | The lowest dose of digoxin should initially be prescribed. The serum digoxin concentrations should be monitored and used for titration of digoxin dose to obtain the desired clinical effect. |
|
warfarin |
↓ warfarin ↔ darunavir |
Warfarin concentrations are decreased when co-administered with PREZISTA/ritonavir. It is recommended that the international normalized ratio (INR) be monitored when warfarin is combined with PREZISTA/ritonavir. |
|
carbamazepine |
↔ darunavir ↑ carbamazepine |
The dose of either darunavir/ritonavir or carbamazepine does not need to be adjusted when initiating co-administration with darunavir/ritonavir and carbamazepine. Clinical monitoring of carbamazepine concentrations and its dose titration is recommended to achieve the desired clinical response. |
|
phenobarbital, phenytoin |
↔ darunavir ↓ phenytoin ↓ phenobarbital |
Co-administration of PREZISTA/ritonavir may cause a decrease in the steady-state concentrations of phenytoin and phenobarbital. Phenytoin and phenobarbital levels should be monitored when co-administering with PREZISTA/ritonavir. |
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trazodone, desipramine |
↑ trazodone ↑ desipramine |
Concomitant use of trazodone or desipramine and PREZISTA/ritonavir may increase plasma concentrations of trazodone or desipramine which may lead to adverse events such as nausea, dizziness, hypotension and syncope. If trazodone or desipramine is used with PREZISTA/ritonavir, the combination should be used with caution, and a lower dose of trazodone or desipramine should be considered. |
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clarithromycin |
↔ darunavir ↑ clarithromycin |
No dose adjustment of the combination is required for patients with normal renal function. For patients with renal impairment, the following dose adjustments should be considered:
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ketoconazole, itraconazole, voriconazole |
↑ ketoconazole ↑ darunavir ↑ itraconazole (not studied) ↓ voriconazole (not studied) |
Ketoconazole and itraconazole are potent inhibitors as well as substrates of CYP3A. Concomitant systemic use of ketoconazole, itraconazole, and darunavir/ritonavir may increase plasma concentration of darunavir. |
| Plasma concentrations of ketoconazole or itraconazole may be increased in the presence of darunavir/ritonavir. When co-administration is required, the daily dose of ketoconazole or itraconazole should not exceed 200 mg. | ||
| Plasma concentrations of voriconazole may be decreased in the presence of darunavir/ritonavir. Voriconazole should not be administered to patients receiving darunavir/ritonavir unless an assessment of the benefit/risk ratio justifies the use of voriconazole. | ||
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colchicine |
↑ colchicine |
0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days. If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Patients with renal or hepatic impairment should not be given colchicine with PREZISTA/ritonavir. |
|
artemether/lumefantrine |
↓ artemether ↓ dihydroartemisinin ↑ lumefantrine ↔ darunavir |
The combination of PREZISTA and artemether/lumefantrine can be used without dose adjustments. However, the combination should be used with caution as increased lumefantrine exposure may increase the risk of QT prolongation. |
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rifabutin |
↑ darunavir ↑ rifabutin ↑ 25- |
Dose reduction of rifabutin by at least 75% of the usual dose (300 mg once daily) is recommended (i.e., a maximum dose of 150 mg every other day). Increased monitoring for adverse events is warranted in patients receiving this combination and further dose reduction of rifabutin may be necessary. |
| The reference regimen for rifabutin was 300 mg once daily | ||
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metoprolol, timolol |
↑ beta-blockers | Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir. |
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parenterally administered midazolam |
↑ midazolam | Concomitant use of parenteral midazolam with PREZISTA/ritonavir may increase plasma concentrations of midazolam. Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Co-administration of oral midazolam with PREZISTA/ritonavir is CONTRAINDICATED. |
|
felodipine, nifedipine, nicardipine |
↑ calcium channel blockers | Plasma concentrations of calcium channel blockers (e.g., felodipine, nifedipine, nicardipine) may increase when PREZISTA/ritonavir are co-administered. Caution is warranted and clinical monitoring of patients is recommended. |
|
dexamethasone |
↓ darunavir | Systemic dexamethasone induces CYP3A and can thereby decrease darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA. |
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fluticasone |
↑ fluticasone | Concomitant use of inhaled fluticasone and PREZISTA/ritonavir may increase plasma concentrations of fluticasone. Alternatives should be considered, particularly for long-term use. |
|
bosentan |
↑ bosentan |
In patients who have been receiving PREZISTA/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of PREZISTA/ritonavir. After at least 10 days following the initiation of PREZISTA/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. |
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NS3-4A protease inhibitors: boceprevir telaprevir |
↓ darunavir ↓ boceprevir ↓ telaprevir |
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pravastatin, atorvastatin, rosuvastatin |
↑ pravastatin ↑ atorvastatin ↑ rosuvastatin |
Titrate atorvastatin, pravastatin or rosuvastatin dose carefully and use the lowest necessary dose while monitoring for safety. Do not exceed atorvastatin 20 mg/day. |
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cyclosporine, tacrolimus, sirolimus |
↑ immunosuppressants | Plasma concentrations of cyclosporine, tacrolimus or sirolimus may be increased when co-administered with PREZISTA/ritonavir. Therapeutic concentration monitoring of the immunosuppressive agent is recommended when co-administered with PREZISTA/ritonavir. |
|
salmeterol |
↑ salmeterol | Concurrent administration of salmeterol and PREZISTA/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
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methadone, buprenorphine, buprenorphine/naloxone |
↓ methadone ↔ buprenorphine, naloxone ↑ norbuprenorphine (metabolite) |
No adjustment of methadone dosage is required when initiating co-administration of PREZISTA/ritonavir. However, clinical monitoring is recommended as the dose of methadone during maintenance therapy may need to be adjusted in some patients. No dose adjustment for buprenorphine or buprenorphine/naloxone is required with concurrent administration of PREZISTA/ritonavir. Clinical monitoring is recommended if PREZISTA/ritonavir and buprenorphine or buprenorphine/naloxone are coadministered. |
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risperidone, thioridazine |
↑ neuroleptics | A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir. |
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ethinyl estradiol, norethindrone |
↓ ethinyl estradiol ↓ norethindrone |
Plasma concentrations of ethinyl estradiol are decreased due to induction of its metabolism by ritonavir. Alternative methods of nonhormonal contraception are recommended. |
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sildenafil, vardenafil, tadalafil |
↑ PDE-5 inhibitors (only the use of sildenafil at doses used for treatment of erectile dysfunction has been studied with PREZISTA/ritonavir) |
Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg dose in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours can be used with increased monitoring for PDE-5 inhibitor-associated adverse events. |
|
sertraline, paroxetine |
↔ darunavir ↓ sertraline ↓ paroxetine |
If sertraline or paroxetine is co-administered with PREZISTA/ritonavir, the recommended approach is a careful dose titration of the SSRI based on a clinical assessment of antidepressant response. In addition, patients on a stable dose of sertraline or paroxetine who start treatment with PREZISTA/ritonavir should be monitored for antidepressant response. |
| Coadministered Drug | Dosing Schedule | Effect on ActiveMoiety (Risperidone + 9- Hydroxy-Risperidone(Ratio*) | Risperidone DoseRecommendation | ||
| Coadministered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6)Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 mg twicedaily | 1.4 | 1.5 | Re-evaluate dosing. Donot exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Donot exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards.Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A)Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four timesdaily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
| Coadministered Drug | Dosing Schedule | Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio |
Risperidone Dose Recommendation | ||
|---|---|---|---|---|---|
| Coadministered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6) Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 mg twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/ PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient's usual dose |
| Enzyme (CYP3A) Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
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| Antacids, sucralfate, multivitamins, and other products containing multivalent cations | Moxifloxacin absorption is decreased. Administer AVELOX Tablet at least 4 hours before or 8 hours after these products. ( |
| Warfarin | Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. ( |
| Class IA and Class III antiarrhythmics: | Proarrhythmic effect may be enhanced. Avoid concomitant use. ( |
| Enzyme | Inhibitors | Inducers |
|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
| Drug Class | Specific Drugs |
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
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| Amiodarone Iodide (including iodine- containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
| Concomitant Drug Class: Drug Name |
Effect on Concentration of Etravirine or Concomitant Drug | Clinical Comment |
|---|---|---|
| ↑ = increase, ↓ = decrease, ↔ = no change | ||
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| efavirenz nevirapine |
↓ etravirine | Combining two NNRTIs has not been shown to be beneficial. Concomitant use of INTELENCE® with efavirenz or nevirapine may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and other NNRTIs should not be co-administered. |
| delavirdine | ↑ etravirine | Combining two NNRTIs has not been shown to be beneficial. INTELENCE® and delavirdine should not be co-administered. |
| rilpivirine | ↓ rilpivirine ↔ etravirine |
Combining two NNRTIs has not been shown to be beneficial. INTELENCE® and rilpivirine should not be coadministered. |
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| atazanavir (without ritonavir) |
↓ atazanavir | Concomitant use of INTELENCE® with atazanavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of atazanavir. INTELENCE® should not be co-administered with atazanavir without low-dose ritonavir. |
| atazanavir/ritonavir |
↓ atazanavir ↑ etravirine |
Concomitant use of INTELENCE® with atazanavir/ritonavir may cause a significant decrease in atazanavir Cmin and loss of therapeutic effect of atazanavir. In addition, the mean systemic exposure (AUC) of etravirine after co-administration of INTELENCE® with atazanavir/ritonavir is anticipated to be higher than the mean systemic exposure of etravirine observed in the Phase 3 trials after co-administration of INTELENCE® and darunavir/ritonavir (as part of the background regimen). INTELENCE® and atazanavir/ritonavir should not be co-administered. |
| darunavir/ritonavir |
↓ etravirine | The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE® was co-administered with darunavir/ritonavir. Because all subjects in the Phase 3 trials received darunavir/ritonavir as part of the background regimen and etravirine exposures from these trials were determined to be safe and effective, INTELENCE® and darunavir/ritonavir can be co-administered without dose adjustments. |
| fosamprenavir (without ritonavir) |
↑ amprenavir | Concomitant use of INTELENCE® with fosamprenavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of amprenavir. INTELENCE® should not be co-administered with fosamprenavir without low-dose ritonavir. |
| fosamprenavir/ritonavir |
↑ amprenavir | Due to a significant increase in the systemic exposure of amprenavir, the appropriate doses of the combination of INTELENCE® and fosamprenavir/ritonavir have not been established. INTELENCE® and fosamprenavir/ritonavir should not be co-administered. |
| indinavir (without ritonavir) |
↓ indinavir | Concomitant use of INTELENCE® with indinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of indinavir. INTELENCE® should not be co-administered with indinavir without low-dose ritonavir. |
| lopinavir/ritonavir |
↓ etravirine | The mean systemic exposure (AUC) of etravirine was reduced after co-administration of INTELENCE® with lopinavir/ritonavir (tablet). Because the reduction in the mean systemic exposures of etravirine in the presence of lopinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE® and lopinavir/ritonavir can be co-administered without dose adjustments. |
| nelfinavir (without ritonavir) |
↑ nelfinavir | Concomitant use of INTELENCE® with nelfinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of nelfinavir. INTELENCE® should not be co-administered with nelfinavir without low-dose ritonavir. |
| ritonavir |
↓ etravirine | Concomitant use of INTELENCE® with ritonavir 600 mg twice daily may cause a significant decrease in the plasma concentration of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and ritonavir 600 mg twice daily should not be co-administered. |
| saquinavir/ritonavir |
↓ etravirine | The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE® was co-administered with saquinavir/ritonavir. Because the reduction in the mean systemic exposures of etravirine in the presence of saquinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE® and saquinavir/ritonavir can be co-administered without dose adjustments. |
| tipranavir/ritonavir |
↓ etravirine | Concomitant use of INTELENCE® with tipranavir/ritonavir may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and tipranavir/ritonavir should not be co-administered. |
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| maraviroc |
↔ etravirine ↓ maraviroc |
When INTELENCE® is co-administered with maraviroc in the absence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 600 mg twice daily. No dose adjustment of INTELENCE® is needed. |
| maraviroc/darunavir/ritonavir |
↔ etravirine ↑ maraviroc |
When INTELENCE® is co-administered with maraviroc in the presence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 150 mg twice daily. No dose adjustment of INTELENCE® is needed. |
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digoxin |
↔ etravirine ↑ digoxin |
For patients who are initiating a combination of INTELENCE® and digoxin, the lowest dose of digoxin should initially be prescribed. For patients on a stable digoxin regimen and initiating INTELENCE®, no dose adjustment of either INTELENCE® or digoxin is needed. The serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect. |
| amiodarone, bepridil, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine |
↓ antiarrhythmics | Concentrations of these antiarrhythmics may be decreased when co-administered with INTELENCE®. INTELENCE® and antiarrhythmics should be co-administered with caution. Drug concentration monitoring is recommended, if available. |
|
warfarin |
↑ anticoagulants | Warfarin concentrations may be increased when co-administered with INTELENCE®. The international normalized ratio (INR) should be monitored when warfarin is combined with INTELENCE®. |
|
carbamazepine, phenobarbital, phenytoin |
↓ etravirine | Carbamazepine, phenobarbital and phenytoin are inducers of CYP450 enzymes. INTELENCE® should not be used in combination with carbamazepine, phenobarbital, or phenytoin as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®. |
|
fluconazole voriconazole |
↑ etravirine ↔ fluconazole ↑ voriconazole |
Co-administration of etravirine and fluconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and fluconazole should be co-administered with caution. No dose adjustment of INTELENCE® or fluconazole is needed. |
| Co-administration of etravirine and voriconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and voriconazole should be co-administered with caution. No dose adjustment of INTELENCE® or voriconazole is needed. | ||
|
itraconazole, ketoconazole, posaconazole |
↑ etravirine ↓ itraconazole ↓ ketoconazole ↔ posaconazole |
Posaconazole, a potent inhibitor of CYP3A4, may increase plasma concentrations of etravirine. Itraconazole and ketoconazole are potent inhibitors as well as substrates of CYP3A4. Concomitant systemic use of itraconazole or ketoconazole and INTELENCE® may increase plasma concentrations of etravirine. Simultaneously, plasma concentrations of itraconazole or ketoconazole may be decreased by INTELENCE®. Dose adjustments for itraconazole, ketoconazole or posaconazole may be necessary depending on the other co-administered drugs. |
|
clarithromycin |
↑ etravirine ↓ clarithromycin ↑ 14-OH-clarithromycin |
Clarithromycin exposure was decreased by INTELENCE®; however, concentrations of the active metabolite, 14-hydroxy-clarithromycin, were increased. Because 14-hydroxy-clarithromycin has reduced activity against |
|
artemether/lumefantrine |
↔ etravirine ↓ artemether ↓ dihydroartemisinin ↓ lumefantrine |
Caution is warranted when co-administering INTELENCE® and artemether/lumefantrine as it is unknown whether the decrease in exposure of artemether or its active metabolite, dihydroartemisinin, could result in decreased antimalarial efficacy. No dose adjustment is needed for INTELENCE®. |
|
rifampin, rifapentine |
↓ etravirine | Rifampin and rifapentine are potent inducers of CYP450 enzymes. INTELENCE® should not be used with rifampin or rifapentine as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®. |
|
rifabutin |
↓ etravirine ↓ rifabutin ↓ 25- |
If INTELENCE® is NOT co-administered with a protease inhibitor/ritonavir, then rifabutin at a dose of 300 mg once daily is recommended. If INTELENCE® is co-administered with darunavir/ritonavir, lopinavir/ritonavir or saquinavir/ritonavir, then rifabutin should not be co-administered due to the potential for significant reductions in etravirine exposure. |
|
diazepam |
↑ diazepam | Concomitant use of INTELENCE® with diazepam may increase plasma concentrations of diazepam. A decrease in diazepam dose may be needed. |
|
dexamethasone (systemic) |
↓ etravirine | Systemic dexamethasone induces CYP3A and can decrease etravirine plasma concentrations. This may result in loss of therapeutic effect of INTELENCE®. Systemic dexamethasone should be used with caution or alternatives should be considered, particularly for long-term use. |
|
St. John's wort ( |
↓ etravirine | Concomitant use of INTELENCE® with products containing St. John's wort may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®. INTELENCE® and products containing St. John's wort should not be co-administered. |
|
telaprevir |
↔ etravirine ↓ telaprevir |
There are insufficient data to make a dosing recommendation for telaprevir when used with INTELENCE®. |
|
atorvastatin fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin |
↔ etravirine ↓ atorvastatin ↑ 2-OH-atorvastatin ↔ etravirine ↑ fluvastatin, ↓ lovastatin, ↑ pitavastatin, ↔ pravastatin, ↔ rosuvastatin, ↓ simvastatin |
The combination of INTELENCE® and atorvastatin can be given without dose adjustments, however, the dose of atorvastatin may need to be altered based on clinical response. No interaction between pravastatin, rosuvastatin and INTELENCE® is expected. Lovastatin and simvastatin are CYP3A substrates and co-administration with INTELENCE® may result in lower plasma concentrations of the HMG-CoA reductase inhibitor. Fluvastatin and pitavastatin are metabolized by CYP2C9 and co-administration with INTELENCE® may result in higher plasma concentrations of the HMG-CoA reductase inhibitor. Dose adjustments for these HMG-CoA reductase inhibitors may be necessary. |
|
cyclosporine, sirolimus, tacrolimus |
↓ immunosuppressant | INTELENCE® and systemic immunosuppressants should be co-administered with caution because plasma concentrations of cyclosporine, sirolimus, or tacrolimus may be affected. |
|
buprenorphine, buprenorphine/naloxone methadone |
↔ etravirine ↓ buprenorphine ↔ norbuprenorphine ↔ methadone |
INTELENCE® and buprenorphine (or buprenorphine/naloxone) can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as buprenorphine (or buprenorphine/naloxone) maintenance therapy may need to be adjusted in some patients. INTELENCE® and methadone can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as methadone maintenance therapy may need to be adjusted in some patients. |
|
sildenafil tadalafil, vardenafil |
↓ sildenafil ↓ N-desmethyl-sildenafil |
INTELENCE® and sildenafil can be co-administered without dose adjustments, however, the dose of sildenafil may need to be altered based on clinical effect. |
|
clopidogrel |
↓ clopidogrel (active) metabolite | Activation of clopidogrel to its active metabolite may be decreased when clopidogrel is co-administered with INTELENCE®. Alternatives to clopidogrel should be considered. |
|
|
|
|
|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
|
|
|
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
| albuterol, systemic and inhaled | lomefloxacin |
| amoxicillin | mebendazole |
| ampicillin, with or without sulbactam | medroxyprogesterone |
| atenolol | methylprednisolone |
| azithromycin | metronidazole |
| caffeine, dietary ingestion | metoprolol |
| cefaclor | nadolol |
| co-trimoxazole (trimethoprim and sulfamethoxazole) | nifedipine |
| diltiazem | nizatidine |
| dirithromycin | norfloxacin |
| enflurane | ofloxacin |
| famotidine | omeprazole |
| felodipine | prednisone, prednisolone |
| finasteride | ranitidine |
| hydrocortisone | rifabutin |
| isoflurane | roxithromycin |
| isoniazid | sorbitol (purgative doses do not inhibit theophylline absorption) |
| isradipine | sucralfate |
| influenza vaccine | terbutaline, systemic |
| ketoconazole | terfenadine |
| tetracycline | |
| tocainide | |
| * Refer to | |
|
|
|
|
| CYP2C9 |
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast |
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 |
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton |
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 |
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton |
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
|
|
|
| Anticoagulants |
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents |
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents |
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors |
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
|
Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide |
|
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels. | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate |
|
Increased lamotrigine concentrations slightly more than 2 fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
| AED Co-administered |
AED Concentration |
Topiramate Concentration |
| Phenytoin |
NC or 25% increasea
|
48% decrease |
| Carbamazepine (CBZ) |
NC |
40% decrease |
| CBZ epoxideb
|
NC |
NE |
| Valproic acid |
11% decrease |
14% decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NC at TPM doses up to 400 mg/day |
13% decrease |
|
|
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitors (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
|
|
|
|
| Erythromycin (500 mg every 8 hrs) | +82% | +109% |
| Ketoconazole (400 mg once daily) | +135% | +164% |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Hepatitis C Protease inhibitor (boceprevir) |
|
|
|
See |
|
|
|
| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine,danazol | Do not exceed 10 mg simvastatindaily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Diltiazem | Do not exceed 40 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
|
|
|
|
|
|
| Carbamazepine | 400 to 2000 | 900 | nc |
40% decrease [CI: 17% decrease, 57% decrease] |
| Phenobarbital | 100 to 150 | 600 to 1800 | 14% increase [CI: 2% increase, 24% increase] | 25% decrease [CI: 12% decrease, 51% decrease] |
| Phenytoin | 250 to 500 | 600 to 1800 >1200 to 2400 | nc |
30% decrease [CI: 3% decrease, 48% decease] |
| Valproic acid | 400 to 2800 | 600 to 1800 | nc |
18% decrease [CI: 13% decrease, 40% decrease] |
| Interacting DrugInteracting Drug | InteractionInteraction |
|---|---|
| Interacting Drug | Interaction |
| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents |
Carefully monitor blood glucose ( |
|
|
||
|
|
||
|
|
||
|
|
||
|
|
||
| AED Co-administered |
AED Concentration |
Topiramate Concentration |
| Phenytoin |
NC or 25% increasea
|
48% decrease |
| Carbamazepine (CBZ) |
NC |
40% decrease |
| CBZ epoxideb
|
NC |
NE |
| Valproic acid |
11% decrease |
14% decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NC at TPM doses up to 400 mg/day |
13% decrease |
| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| Lopinavir plus ritonavir | Use lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) |
Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
|
|
|
|
|
|
||
| Phenytoin |
NC or 25% increasea
|
48% decrease |
| Carbamazepine (CBZ) |
NC |
40% decrease |
| CBZ epoxideb
|
NC |
NE |
| Valproic acid |
11% decrease |
14% decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NC at TPM doses up to 400 mg/day |
13% decrease |
|
|
|
| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine, danazol | Do not exceed 10 mg simvastatin daily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Diltiazem | Do not exceed 40 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
|
|
|
|
Inflammatory Drugs |
Agents |
|
|
| ciprofloxacin |
melphalan | amphotericin B |
azapropazon |
cimetidine |
tacrolimus |
fibric acid derivatives (e.g., bezafibrate, fenofibrate) |
|
|
|
|
|
|
| diltiazem | fluconazole | azithromycin | methylprednisolone | allopurinol |
| nicardipine | itraconazole | clarithromycin | amiodarone | |
| verapamil | ketoconazole | erythromycin | bromocriptine | |
| quinupristin/ | colchicine | |||
| voriconazole | dalfopristin | danazol | ||
| imatinib | ||||
| metoclopramide | ||||
| nefazodone | ||||
| oral contraceptives |
|
|
|
|
|
| nafcillin | carbamazepine | bosentan | St. John’s Wort |
| rifampin | oxcarbazepine | octreotide | |
| phenobarbital | orlistat | ||
| phenytoin | sulfinpyrazone | ||
| terbinafine | |||
| ticlopidine | |||
| Coadministered Drug | Dosing Schedule | Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio |
Risperidone Dose Recommendation | ||
|---|---|---|---|---|---|
| Coadministered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6) Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 mg twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/ PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient's usual dose |
| Enzyme (CYP3A) Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
|
|
|
(mg) |
|
Pharmacokinetic Parameters (90% CI); No Effect = 1.00 |
||
| Cmax | AUC | Cmin | ||||
| All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated. | ||||||
| Cimetidine | 600 twice daily, 6 days |
400 single dose | 12 | 1.07 (0.77, 1.49) |
0.98 (0.81, 1.19) |
0.82 (0.69, 0.99) |
| Clarithromycin | 500 q12h, 7 days |
800 three times daily, 7 days |
10 | 1.08 (0.85, 1.38) |
1.19 (1.00, 1.42) |
1.57 (1.16, 2.12) |
| Delavirdine | 400 three times daily | 400 three times daily, 7 days |
28 | 0.64 (0.48, 0.86) |
No significant change |
2.18 (1.16, 4.12) |
| Delavirdine | 400 three times daily | 600 three times daily, 7 days |
28 | No significant change | 1.53 (1.07, 2.20) |
3.98 (2.04, 7.78) |
| Efavirenz |
600 once daily, 10 days |
1000 three times daily, 10 days |
20 | |||
| After morning dose | No significant change |
0.67 (0.61, 0.74) |
0.61 (0.49, 0.76) |
|||
| After afternoon dose | No significant change |
0.63 (0.54, 0.74) |
0.48 (0.43, 0.53) |
|||
| After evening dose | 0.71 (0.57, 0.89) |
0.54 (0.46, 0.63) |
0.43 (0.37, 0.50) |
|||
| Fluconazole |
400 once daily, 8 days |
1000 three times daily, 7 days | 11 | 0.87 (0.72, 1.05) |
0.76 (0.59, 0.98) |
0.90 (0.72, 1.12) |
| Grapefruit Juice | 8 oz. | 400 single dose | 10 | 0.65 (0.53, 0.79) |
0.73 (0.60, 0.87) |
0.90 (0.71, 1.15) |
| Isoniazid | 300 once daily in the morning, 8 days |
800 three times daily, 7 days | 11 | 0.95 (0.88, 1.03) |
0.99 (0.87, 1.13) |
0.89 (0.75, 1.06) |
| Itraconazole | 200 twice daily, 7 days |
600 three times daily, 7 days |
12 | 0.78 (0.69, 0.88) |
0.99 (0.91, 1.06) |
1.49 (1.28, 1.74) |
| Ketoconazole | 400 once daily, 7 days |
600 three times daily, 7 days |
12 | 0.69 (0.61, 0.78) |
0.80 (0.74, 0.87) |
1.29 (1.11, 1.51) |
| 400 once daily, 7 days |
400 three times daily, 7 days |
12 | 0.42 (0.37, 0.47) |
0.44 (0.41, 0.48) |
0.73 (0.62, 0.85) |
|
| Methadone | 20-60 once daily in the morning, 8 days |
800 three times daily, 8 days |
10 | See text below for discussion of interaction. | ||
| Quinidine | 200 single dose | 400 single dose | 10 | 0.96 (0.79, 1.18) |
1.07 (0.89, 1.28) |
0.93 (0.73, 1.19) |
| Rifabutin | 150 once daily in the morning, 10 days |
800 three times daily, 10 days |
14 | 0.80 (0.72, 0.89) |
0.68 (0.60, 0.76) |
0.60 (0.51, 0.72) |
| Rifabutin | 300 once daily in the morning, 10 days |
800 three times daily, 10 days |
10 | 0.75 (0.61, 0.91) |
0.66 (0.56, 0.77) |
0.61 (0.50, 0.75) |
| Rifampin | 600 once daily in the morning, 8 days |
800 three times daily, 7 days |
12 | 0.13 (0.08, 0.22) |
0.08 (0.06, 0.11) |
Not Done |
| Ritonavir | 100 twice daily, 14 days |
800 twice daily, 14 days |
10, 16 |
See text below for discussion of interaction. | ||
| Ritonavir | 200 twice daily, 14 days |
800 twice daily,14 days |
9, 16 |
See text below for discussion of interaction. | ||
| Sildenafil | 25 single dose | 800 three times daily | 6 | See text below for discussion of interaction. | ||
| St. John's wort ( standardized to 0.3 % hypericin) |
300 three times daily with meals, 14 days |
800 three times daily | 8 | Not Available | 0.46 (0.34, 0.58) |
0.19 (0.06, 0.33) |
| Stavudine (d4T) |
40 twice daily, 7 days |
800 three times daily, 7 days |
11 | 0.95 (0.80, 1.11) |
0.95 (0.80, 1.12) |
1.13 (0.83, 1.53) |
| Trimethoprim/ Sulfamethoxazole |
800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days |
400 four times daily, 7 days |
12 | 1.12 (0.87, 1.46) |
0.98 (0.81, 1.18) |
0.83 (0.72, 0.95) |
| Zidovudine |
200 three times daily, 7 days | 1000 three times daily, 7 days |
12 | 1.06 (0.91, 1.25) |
1.05 (0.86, 1.28) |
1.02 (0.77, 1.35) |
| Zidovudine/ Lamivudine (3TC) |
200/150 three times daily, 7 days |
800 three times daily, 7 days |
6, 9 |
1.05 (0.83, 1.33) |
1.04 (0.67, 1.61) |
0.98 (0.56, 1.73) |
|
|
|
|
|
Pharmacokinetic Parameters (90% CI); No Effect = 1.00 |
||
| Cmax | AUC | Cmin | ||||
| All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated. | ||||||
| Clarithromycin | 500 twice daily, 7 days |
800 three times daily, 7 days | 12 | 1.19 (1.02, 1.39) |
1.47 (1.30, 1.65) |
1.97 (1.58, 2.46) n=11 |
| Efavirenz | 200 once daily, 14 days |
800 three times daily, 14 days | 20 | No significant change | No significant change | -- |
| Ethinyl Estradiol (ORTHO-NOVUM 1/35) |
35 mcg, 8 days | 800 three times daily, 8 days | 18 | 1.02 (0.96, 1.09) |
1.22 (1.15, 1.30) |
1.37 (1.24, 1.51) |
| Isoniazid | 300 once daily in the morning, 8 days |
800 three times daily, 8 days | 11 | 1.34 (1.12, 1.60) |
1.12 (1.03, 1.22) |
1.00 (0.92, 1.08) |
| Methadone |
20-60 once daily in the morning, 8 days |
800 three times daily, 8 days | 12 | 0.93 (0.84, 1.03) |
0.96 (0.86, 1.06) |
1.06 (0.94, 1.19) |
| Norethindrone (ORTHO-NOVUM 1/35) |
1 mcg, 8 days | 800 three times daily, 8 days | 18 | 1.05 (0.95, 1.16) |
1.26 (1.20, 1.31) |
1.44 (1.32, 1.57) |
| Rifabutin •150 mg once daily in the morning, 11 days + indinavir compared to 300 mg once daily in the morning, 11 days alone |
150 once daily in the morning, 10 days 300 once daily in the morning, 10 days |
800 three times daily, 10 days 800 three times daily, 10 days |
14 10 |
1.29 (1.05, 1.59) 2.34 (1.64, 3.35) |
1.54 (1.33, 1.79) 2.73 (1.99, 3.77) |
1.99 (1.71, 2.31) n=13 3.44 (2.65, 4.46) n=9 |
| Ritonavir | 100 twice daily, 14 days |
800 twice daily, 14 days |
10, 4 |
1.61 (1.13, 2.29) |
1.72 (1.20, 2.48) |
1.62 (0.93, 2.85) |
| 200 twice daily, 14 days |
800 twice daily, 14 days |
9, 5 |
1.19 (0.85, 1.66) |
1.96 (1.39, 2.76) |
4.71 (2.66, 8.33) n=9, 4 |
|
| Saquinavir | ||||||
| Hard gel formulation | 600 single dose | 800 three times daily, 2 days | 6 | 4.7 (2.7, 8.1) |
6.0 (4.0, 9.1) |
2.9 (1.7, 4.7) |
| Soft gel formulation | 800 single dose | 800 three times daily, 2 days | 6 | 6.5 (4.7, 9.1) |
7.2 (4.3, 11.9) |
5.5 (2.2, 14.1) |
| Soft gel formulation | 1200 single dose | 800 three times daily, 2 days | 6 | 4.0 (2.7, 5.9) |
4.6 (3.2, 6.7) |
5.5 (3.7, 8.3) |
| Sildenafil | 25 single dose | 800 three times daily | 6 | See text below for discussion of interaction. | ||
| Stavudine |
40 twice daily, 7 days |
800 three times daily, 7 days | 13 | 0.86 (0.73, 1.03) |
1.21 (1.09, 1.33) |
Not Done |
| Theophylline | 250 single dose (on Days 1 and 7) | 800 three times daily, 6 days (Days 2 to 7) | 12, 4 |
0.88 (0.76, 1.03) |
1.14 (1.04, 1.24) |
1.13 (0.86, 1.49) n=7, 3 |
| Trimethoprim/ Sulfamethoxazole |
||||||
| Trimethoprim | 800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days |
400 q6h, 7 days | 12 | 1.18 (1.05, 1.32) |
1.18 (1.05, 1.33) |
1.18 (1.00, 1.39) |
| Trimethoprim/ Sulfamethoxazole |
||||||
| Sulfamethoxazole | 800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days |
400 q6h, 7 days | 12 | 1.01 (0.95, 1.08) |
1.05 (1.01, 1.09) |
1.05 (0.97, 1.14) |
| Vardenafil | 10 single dose | 800 three times daily | 18 | See text below for discussion of interaction. | ||
| Zidovudine |
200 three times daily, 7 days | 1000 three times daily, 7 days | 12 | 0.89 (0.73, 1.09) |
1.17 (1.07, 1.29) |
1.51 (0.71, 3.20) n=4 |
| Zidovudine/ Lamivudine |
||||||
| Zidovudine | 200/150 three times daily, 7 days | 800 three times daily, 7 days | 6, 7 |
1.23 (0.74, 2.03) |
1.39 (1.02, 1.89) |
1.08 (0.77, 1.50) n=5, 5 |
| Zidovudine/ Lamivudine |
||||||
| Lamivudine | 200/150 three times daily, 7 days | 800 three times daily, 7 days | 6, 7 |
0.73 (0.52, 1.02) |
0.91 (0.66, 1.26) |
0.88 (0.59, 1.33) |
| Enzyme | Inhibitors | Inducers |
|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
| Drug Class | Specific Drugs |
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
| Drug | Effect |
| Phenylephrine with prior administration of monoamine oxidase inhibitors (MAOI). | Cardiac pressor response potentiated. May cause acute hypertensive crisis. |
| Phenylephrine with tricyclic antidepressants. | Pressor response increased. |
| Phenylephrine with ergot alkaloids. | Excessive rise in blood pressure. |
| Phenylephrine with bronchodilator sympathomimetic agents and with epinephrine or other sympathomimetics. | Tachycardia or other arrhythmias may occur. |
| Phenylephrine with prior administration of propranolol or other β-adrenergic blockers. | Cardiostimulating effects blocked. |
| Phenylephrine with atropine sulfate. | Reflex bradycardia blocked; pressor response enhanced. |
| Phenylephrine with prior administration of phentolamine or other α-adrenergic blockers. | Pressor response decreased. |
| Phenylephrine with diet preparations, such as amphetamines or phenylpropanolamine. | Synergistic adrenergic response. |
| Concomitant Drug |
Effect on Concentration of Lamotrigine or Concomitant Drug |
Clinical Comment |
| Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine |
Decreased lamotrigine levels approximately 50%. |
| |
↓ levonorgestrel |
Decrease in levonorgestrel component by 19%. |
| Carbamazepine (CBZ) and CBZ epoxide |
↓ lamotrigine |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| |
? CBZ epoxide |
May increase CBZ epoxide levels |
| Phenobarbital/Primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40%. |
| Valproate |
↑ lamotrigine |
Increased lamotrigine concentrations slightly more than 2-fold. |
| |
? valproate |
Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
|
|
|
||
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|
|||
| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
| |
|||
|
|
|||
| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
|
|
|||
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
|
|
|||
|
|
|
||
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
||
|
|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
|
|
|||
|
|
|||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
|
|
|||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
| |
|||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
|
|
|||||
| Coadministered Drug |
Dosing Schedule |
|
Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
|
Risperidone Dose Recommendation |
|
|
Coadministered Drug |
Risperidone |
AUC |
Cm
a
x
|
|
| Enzyme (CYP2D6) Inhibitors |
|
|
|
|
|
| Fluoxetine |
20 mg/day |
2 or 3 mg twice daily |
1.4 |
1.5 |
Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine |
10 mg/day |
4 mg/day |
1.3 |
- |
Re-evaluate dosing. |
|
|
20 mg/day |
4 mg/day |
1.6 |
- |
Do not exceed 8 mg/day |
|
|
40 mg/day |
4 mg/day |
1.8 |
- |
|
| Enzyme (CYP3A/ PgP inducers) |
|
|
|
|
|
| Carbamazepine |
573 ± 168 mg/day |
3 mg twice daily |
0.51 |
0.55 |
Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors |
|
|
|
|
|
| Ranitidine |
150 mg twice daily |
1 mg single dose |
1.2 |
1.4 |
Dose adjustment not needed |
| Cimetidine |
400 mg twice daily |
1 mg single dose |
1.1 |
1.3 |
Dose adjustment not needed |
| Erythromycin |
500 mg four times daily |
1 mg single dose |
1.1 |
0.94 |
Dose adjustment not needed |
| Other Drugs |
|
|
|
|
|
| Amitriptyline |
50 mg twice daily |
3 mg twice daily |
1.2 |
1.1 |
Dose adjustment not needed |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine | Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide | ↓ lamotrigine | Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine | Increased lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
| DRUG | DESCRIPTION OF INTERACTION |
| Sulfonylureas | Hypoglycemia potentiated. |
| Methotrexate | Decreases tubular reabsorption; clinical toxicity from methotrexate can result. |
| Oral Anticoagulants | Increased |
| DRUG | DESCRIPTION OF INTERACTION |
| Corticosteroids | Decreases plasma salicylate level; tapering doses of steroids may promote salicylism. |
| Acidifying Agents | Increases plasma salicylate level. |
| Alkanizing
Agents |
Decreased plasma salicylate levels. |
| DRUG | DESCRIPTION OF INTERACTION |
| Heparin |
Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin treated patients. |
| Pyrazinamide | Inhibits pyrazinamide-induced
hyperuricemia. |
| Uricosuric
Agents |
Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited. |
| LABORATORY
TESTS |
EFFECT OF |
| Thyroid Function | Decreased PBI; |
| Urinary Sugar | False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.). |
| 5-Hydroxyindole acetic acid | False negative with fluorometric test. |
| Acetone, ketone bodies | False positive FeCl3 in Gerhardt reaction; red color persists with boiling. |
| 17-OH
corticosteroids |
False reduced values with >4.8g q.d. salicylate. |
| Vanilmandelic acid | False reduced values. |
| Uric acid | May increase or decrease depending on dose. |
| Prothrombin | Decreased levels; slightly increased prothrombin time. |
| Co-administered Drug | Dosing Schedule | Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (Ratio |
Risperidone Dose Recommendation | ||
| Co-administered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6) Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| ↓= Decreased (induces lamotrigine gluronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ?= Conflicting data. |
||
| Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine | Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide | ↓ lamotrigine | Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine | Increased lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. | |
| Concomitant Drug Class: Drug Name |
Effect on Concentration of Etravirine or Concomitant Drug | Clinical Comment |
|---|---|---|
| ↑ = increase, ↓ = decrease, ↔ = no change | ||
|
|
||
| efavirenz nevirapine |
↓ etravirine | Combining two NNRTIs has not been shown to be beneficial. Concomitant use of INTELENCE® with efavirenz or nevirapine may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and other NNRTIs should not be co-administered. |
| delavirdine | ↑ etravirine | Combining two NNRTIs has not been shown to be beneficial. INTELENCE® and delavirdine should not be co-administered. |
| rilpivirine | ↓ rilpivirine ↔ etravirine |
Combining two NNRTIs has not been shown to be beneficial. INTELENCE® and rilpivirine should not be coadministered. |
|
|
||
| atazanavir (without ritonavir) |
↓ atazanavir | Concomitant use of INTELENCE® with atazanavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of atazanavir. INTELENCE® should not be co-administered with atazanavir without low-dose ritonavir. |
| atazanavir/ritonavir |
↓ atazanavir ↑ etravirine |
Concomitant use of INTELENCE® with atazanavir/ritonavir may cause a significant decrease in atazanavir Cmin and loss of therapeutic effect of atazanavir. In addition, the mean systemic exposure (AUC) of etravirine after co-administration of INTELENCE® with atazanavir/ritonavir is anticipated to be higher than the mean systemic exposure of etravirine observed in the Phase 3 trials after co-administration of INTELENCE® and darunavir/ritonavir (as part of the background regimen). INTELENCE® and atazanavir/ritonavir should not be co-administered. |
| darunavir/ritonavir |
↓ etravirine | The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE® was co-administered with darunavir/ritonavir. Because all subjects in the Phase 3 trials received darunavir/ritonavir as part of the background regimen and etravirine exposures from these trials were determined to be safe and effective, INTELENCE® and darunavir/ritonavir can be co-administered without dose adjustments. |
| fosamprenavir (without ritonavir) |
↑ amprenavir | Concomitant use of INTELENCE® with fosamprenavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of amprenavir. INTELENCE® should not be co-administered with fosamprenavir without low-dose ritonavir. |
| fosamprenavir/ritonavir |
↑ amprenavir | Due to a significant increase in the systemic exposure of amprenavir, the appropriate doses of the combination of INTELENCE® and fosamprenavir/ritonavir have not been established. INTELENCE® and fosamprenavir/ritonavir should not be co-administered. |
| indinavir (without ritonavir) |
↓ indinavir | Concomitant use of INTELENCE® with indinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of indinavir. INTELENCE® should not be co-administered with indinavir without low-dose ritonavir. |
| lopinavir/ritonavir |
↓ etravirine | The mean systemic exposure (AUC) of etravirine was reduced after co-administration of INTELENCE® with lopinavir/ritonavir (tablet). Because the reduction in the mean systemic exposures of etravirine in the presence of lopinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE® and lopinavir/ritonavir can be co-administered without dose adjustments. |
| nelfinavir (without ritonavir) |
↑ nelfinavir | Concomitant use of INTELENCE® with nelfinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of nelfinavir. INTELENCE® should not be co-administered with nelfinavir without low-dose ritonavir. |
| ritonavir |
↓ etravirine | Concomitant use of INTELENCE® with ritonavir 600 mg twice daily may cause a significant decrease in the plasma concentration of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and ritonavir 600 mg twice daily should not be co-administered. |
| saquinavir/ritonavir |
↓ etravirine | The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE® was co-administered with saquinavir/ritonavir. Because the reduction in the mean systemic exposures of etravirine in the presence of saquinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE® and saquinavir/ritonavir can be co-administered without dose adjustments. |
| tipranavir/ritonavir |
↓ etravirine | Concomitant use of INTELENCE® with tipranavir/ritonavir may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE®. INTELENCE® and tipranavir/ritonavir should not be co-administered. |
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| maraviroc |
↔ etravirine ↓ maraviroc |
When INTELENCE® is co-administered with maraviroc in the absence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 600 mg twice daily. No dose adjustment of INTELENCE® is needed. |
| maraviroc/darunavir/ritonavir |
↔ etravirine ↑ maraviroc |
When INTELENCE® is co-administered with maraviroc in the presence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 150 mg twice daily. No dose adjustment of INTELENCE® is needed. |
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digoxin |
↔ etravirine ↑ digoxin |
For patients who are initiating a combination of INTELENCE® and digoxin, the lowest dose of digoxin should initially be prescribed. For patients on a stable digoxin regimen and initiating INTELENCE®, no dose adjustment of either INTELENCE® or digoxin is needed. The serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect. |
| amiodarone, bepridil, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine |
↓ antiarrhythmics | Concentrations of these antiarrhythmics may be decreased when co-administered with INTELENCE®. INTELENCE® and antiarrhythmics should be co-administered with caution. Drug concentration monitoring is recommended, if available. |
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warfarin |
↑ anticoagulants | Warfarin concentrations may be increased when co-administered with INTELENCE®. The international normalized ratio (INR) should be monitored when warfarin is combined with INTELENCE®. |
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carbamazepine, phenobarbital, phenytoin |
↓ etravirine | Carbamazepine, phenobarbital and phenytoin are inducers of CYP450 enzymes. INTELENCE® should not be used in combination with carbamazepine, phenobarbital, or phenytoin as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®. |
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fluconazole voriconazole |
↑ etravirine ↔ fluconazole ↑ voriconazole |
Co-administration of etravirine and fluconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and fluconazole should be co-administered with caution. No dose adjustment of INTELENCE® or fluconazole is needed. |
| Co-administration of etravirine and voriconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and voriconazole should be co-administered with caution. No dose adjustment of INTELENCE® or voriconazole is needed. | ||
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itraconazole, ketoconazole, posaconazole |
↑ etravirine ↓ itraconazole ↓ ketoconazole ↔ posaconazole |
Posaconazole, a potent inhibitor of CYP3A4, may increase plasma concentrations of etravirine. Itraconazole and ketoconazole are potent inhibitors as well as substrates of CYP3A4. Concomitant systemic use of itraconazole or ketoconazole and INTELENCE® may increase plasma concentrations of etravirine. Simultaneously, plasma concentrations of itraconazole or ketoconazole may be decreased by INTELENCE®. Dose adjustments for itraconazole, ketoconazole or posaconazole may be necessary depending on the other co-administered drugs. |
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clarithromycin |
↑ etravirine ↓ clarithromycin ↑ 14-OH-clarithromycin |
Clarithromycin exposure was decreased by INTELENCE®; however, concentrations of the active metabolite, 14-hydroxy-clarithromycin, were increased. Because 14-hydroxy-clarithromycin has reduced activity against |
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rifampin, rifapentine |
↓ etravirine | Rifampin and rifapentine are potent inducers of CYP450 enzymes. INTELENCE® should not be used with rifampin or rifapentine as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®. |
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rifabutin |
↓ etravirine ↓ rifabutin ↓ 25- |
If INTELENCE® is NOT co-administered with a protease inhibitor/ritonavir, then rifabutin at a dose of 300 mg once daily is recommended. If INTELENCE® is co-administered with darunavir/ritonavir, lopinavir/ritonavir or saquinavir/ritonavir, then rifabutin should not be co-administered due to the potential for significant reductions in etravirine exposure. |
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diazepam |
↑ diazepam | Concomitant use of INTELENCE® with diazepam may increase plasma concentrations of diazepam. A decrease in diazepam dose may be needed. |
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dexamethasone (systemic) |
↓ etravirine | Systemic dexamethasone induces CYP3A and can decrease etravirine plasma concentrations. This may result in loss of therapeutic effect of INTELENCE®. Systemic dexamethasone should be used with caution or alternatives should be considered, particularly for long-term use. |
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St. John's wort ( |
↓ etravirine | Concomitant use of INTELENCE® with products containing St. John's wort may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE®. INTELENCE® and products containing St. John's wort should not be co-administered. |
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atorvastatin fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin |
↔ etravirine ↓ atorvastatin ↑ 2-OH-atorvastatin ↔ etravirine ↑ fluvastatin, ↓ lovastatin, ↑ pitavastatin, ↔ pravastatin, ↔ rosuvastatin, ↓ simvastatin |
The combination of INTELENCE® and atorvastatin can be given without dose adjustments, however, the dose of atorvastatin may need to be altered based on clinical response. No interaction between pravastatin, rosuvastatin and INTELENCE® is expected. Lovastatin and simvastatin are CYP3A substrates and co-administration with INTELENCE® may result in lower plasma concentrations of the HMG-CoA reductase inhibitor. Fluvastatin and pitavastatin are metabolized by CYP2C9 and co-administration with INTELENCE® may result in higher plasma concentrations of the HMG-CoA reductase inhibitor. Dose adjustments for these HMG-CoA reductase inhibitors may be necessary. |
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cyclosporine, sirolimus, tacrolimus |
↓ immunosuppressant | INTELENCE® and systemic immunosuppressants should be co-administered with caution because plasma concentrations of cyclosporine, sirolimus, or tacrolimus may be affected. |
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buprenorphine, buprenorphine/naloxone methadone |
↔ etravirine ↓ buprenorphine ↔ norbuprenorphine ↔ methadone |
INTELENCE® and buprenorphine (or buprenorphine/naloxone) can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as buprenorphine (or buprenorphine/naloxone) maintenance therapy may need to be adjusted in some patients. INTELENCE® and methadone can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as methadone maintenance therapy may need to be adjusted in some patients. |
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sildenafil tadalafil, vardenafil |
↓ sildenafil ↓ N-desmethyl-sildenafil |
INTELENCE® and sildenafil can be co-administered without dose adjustments, however, the dose of sildenafil may need to be altered based on clinical effect. |
|
clopidogrel |
↓ clopidogrel (active) metabolite | Activation of clopidogrel to its active metabolite may be decreased when clopidogrel is co-administered with INTELENCE®. Alternatives to clopidogrel should be considered. |
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|
(Peak plasma concentration) |
(Extent of systemic exposure) |
|---|---|---|
| Erythromycin (500 mg every 8 hrs) |
+82% | +109% |
| Ketoconazole (400 mg once daily) |
+135% | +164% |
|
|
|
| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine, danazol | Do not exceed 10 mg simvastatin daily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Diltiazem | Do not exceed 40 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
| Concomitant Drug Class: Drug Name | Effect on Concentration |
Clinical Comment |
|---|---|---|
|
Antacids |
↓ elvitegravir | Elvitegravir plasma concentrations are lower when STRIBILD is administered simultaneously with antacids. It is recommended to separate STRIBILD and antacid administration by at least 2 hours. |
|
H2 Receptor Antagonists |
⇔ elvitegravir | No dose adjustment is needed when STRIBILD is combined with either H2 receptor antagonists or proton pump inhibitors. |
|
e.g. amiodarone bepridil digoxin disopyramide flecainide systemic lidocaine mexiletine propafenone quinidine |
↑ antiarrhythmics ↑ digoxin |
Concentrations of these antiarrhythmic drugs may be increased when coadministered with STRIBILD. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when coadministered with STRIBILD. |
|
clarithromycin telithromycin |
↑ clarithromycin ↑ telithromycin ↑ cobicistat |
Concentrations of clarithromycin and/or cobicistat may be altered when clarithromycin is coadministered with STRIBILD. No dose adjustment of clarithromycin is required. The dose of clarithromycin should be reduced by 50%. Concentrations of telithromycin and/or cobicistat may be increased when telithromycin is coadministered with STRIBILD. |
|
warfarin |
Effect on warfarin unknown | Concentrations of warfarin may be affected upon coadministration with STRIBILD. It is recommended that the international normalized ratio (INR) be monitored upon coadministration with STRIBILD. |
|
carbamazepine oxcarbazepine phenobarbital phenytoin |
↑ carbamazepine ↓ elvitegravir ↓ cobicistat |
Coadministration of carbamazepine, oxcarbazepine, phenobarbital, or phenytoin with STRIBILD may significantly decrease cobicistat and elvitegravir plasma concentrations, which may result in loss of therapeutic effect and development of resistance. Alternative anticonvulsants should be considered. |
| clonazepam ethosuximide |
↑ clonazepam ↑ ethosuximide |
Concentrations of clonazepam and ethosuximide may be increased when coadministered with STRIBILD. Clinical monitoring is recommended upon coadministration with STRIBILD. |
|
Selective Serotonin Reuptake Inhibitors (SSRIs) e.g. paroxetine Tricyclic Antidepressants (TCAs) e.g. amitriptyline desipramine imipramine nortriptyline buproprion trazodone |
↑ SSRIs ↑ TCAs ↑ trazodone |
Concentrations of these antidepressant agents may be increased when coadministered with STRIBILD. Careful dose titration of the antidepressant and monitoring for antidepressant response is recommended. |
|
itraconazole ketoconazole voriconazole |
↑ elvitegravir ↑ cobicistat ↑ itraconazole ↑ ketoconazole ↑voriconazole |
Concentrations of ketoconazole, itraconazole and voriconazole may increase upon coadministration with STRIBILD. When administering with STRIBILD, the maximum daily dose of ketoconazole or itraconazole should not exceed 200 mg per day. An assessment of benefit/risk ratio is recommended to justify use of voriconazole with STRIBILD. |
|
colchicine |
↑ colchicine |
STRIBILD should not be coadministered with colchicine to patients with renal or hepatic impairment. 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days. If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). |
|
rifabutin rifapentine |
↓ elvitegravir ↓ cobicistat |
Coadministration of rifabutin and rifapentine with STRIBILD may significantly decrease elvitegravir and cobicistat plasma concentrations, which may result in loss of therapeutic effect and development of resistance. Coadministration of STRIBILD with rifabutin or rifapentine is not recommended. |
|
e.g. metoprolol timolol |
↑ beta-blockers | Concentrations of beta-blockers may be increased when coadministered with STRIBILD. Clinical monitoring is recommended and a dose decrease of the beta blocker may be necessary when these agents are coadministered with STRIBILD. |
|
e.g. amlodipine diltiazem felodipine nicardipine nifedipine verapamil |
↑ calcium channel blockers | Concentrations of calcium channel blockers may be increased when coadministered with STRIBILD. Caution is warranted and clinical monitoring is recommended upon coadministration with STRIBILD. |
|
Systemic: dexamethasone |
↓ elvitegravir ↓ cobicistat |
Systemic dexamethasone, a CYP3A inducer, may significantly decrease elvitegravir and cobicistat plasma concentrations, which may result in loss of therapeutic effect and development of resistance. |
|
Inhaled/Nasal: fluticasone |
↑ fluticasone | Concomitant use of inhaled or nasal fluticasone and STRIBILD may increase plasma concentrations of fluticasone, resulting in reduced serum cortisol concentrations. Alternative corticosteroids should be considered, particularly for long term use. |
|
bosentan |
↑ bosentan |
In patients who have been receiving STRIBILD for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of STRIBILD. After at least 10 days following the initiation of STRIBILD, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. |
|
atorvastatin |
↑ atorvastatin |
Initiate with the lowest starting dose of atorvastatin and titrate carefully while monitoring for safety. |
|
norgestimate/ethinyl estradiol |
↑ norgestimate ↓ ethinyl estradiol |
The effects of increases in the concentration of the progestational component norgestimate are not fully known and can include increased risk of insulin resistance, dyslipidemia, acne, and venous thrombosis. The potential risks and benefits associated with coadministration of norgestimate/ethinyl estradiol with STRIBILD should be considered, particularly in women who have risk factors for these events. Coadministration of STRIBILD with other hormonal contraceptives (e.g., contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than norgestimate has not been studied; therefore, alternative (non hormonal) methods of contraception can be considered. |
|
e.g. cyclosporine sirolimus tacrolimus |
↑ immuno-suppressants | Concentrations of these immunosuppressant agents may be increased when coadministered with STRIBILD. Therapeutic monitoring of the immunosuppressive agents is recommended upon coadministration with STRIBILD. |
|
salmeterol |
↑ salmeterol | Coadministration of salmeterol and STRIBILD is not recommended. Coadministration of salmeterol with STRIBILD may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia. |
|
e.g. perphenazine risperidone thioridazine |
↑ neuroleptics | A decrease in dose of the neuroleptic may be needed when coadministered with STRIBILD. |
|
sildenafil tadalafil vardenafil |
↑ PDE5 inhibitors | Coadministration with STRIBILD may result in an increase in PDE-5 inhibitor associated adverse events, including hypotension, syncope, visual disturbances, and priapism.
Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 72 hours, or tadalafil at a single dose not exceeding 10 mg in 72 hours can be used with increased monitoring for PDE-5 inhibitor associated with adverse events. |
|
Benzodiazepines: e.g. Parenterally administered midazolam clorazepate diazepam estazolam flurazepam buspirone zolpidem |
↑ sedatives/hypnotics |
Concomitant use of parenteral midazolam with STRIBILD may increase plasma concentrations of midazolam. Coadministration should be done in a setting that ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Coadministration of oral midazolam with STRIBILD is contraindicated. With other sedative/hypnotics, dose reduction may be necessary and clinical monitoring is recommended. |
| albuterol, | felodipine | norfloxacin |
| systemic and inhaled | finasteride | ofloxacin |
| amoxicillin | hydrocortisone | omeprazole |
| ampicillin, | isoflurane | prednisone, prednisolone |
| with or without sulbactam | isoniazid | ranitidine |
| atenolol | isradipine | rifabutin |
| azithromycin | influenza vaccine | roxithromycin |
| caffeine, | ketoconazole | sorbitol |
| dietary ingestion | lomefloxacin | (purgative doses do not |
| cefaclor | mebendazole | inhibit theophylline |
| co-trimoxazole | medroxyprogesterone | absorption) |
| (trimethoprim | methylprednisolone | sucralfate |
| sulfamethoxazole) | metronidazole | terbutaline, systemic |
| diltiazem | metoprolol | terfenadine |
| dirithromycin | nadolol | tetracycline |
| enflurane | nifedipine | tocainide |
| famotidine | nizatidine | |
| AED Co-administered | AED Concentration | Topiramate Concentration |
| Phenytoin | NC or 25% increasea | 48% decrease |
| Carbamazepine (CBZ) | NC | 40% decrease |
| CBZ epoxideb | NC | NE |
| Valproic acid | 11% decrease | 14% decrease |
| Phenobarbital | NC | NE |
| Primidone | NC | NE |
| Lamotrigine | NC at TPM doses up to 400 mg/day | 13% decrease |
| Drug or Drug Class | Effect |
|---|---|
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| Dopamine / Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥100 mg/day or equivalent); Octreotide (>100 mcg/day). |
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
|
|
|
| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
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|
|
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone > 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms. |
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| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
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| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
| Coadministered Drug |
Dosing Schedule |
|
Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
|
Risperidone Dose Recommendation |
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|
Coadministered Drug |
Risperidone |
AUC |
Cm
a
x
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| Enzyme (CYP2D6) Inhibitors |
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| Fluoxetine |
20 mg/day |
2 or 3 mg twice daily |
1.4 |
1.5 |
Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine |
10 mg/day |
4 mg/day |
1.3 |
- |
Re-evaluate dosing. |
|
|
20 mg/day |
4 mg/day |
1.6 |
- |
Do not exceed 8 mg/day |
|
|
40 mg/day |
4 mg/day |
1.8 |
- |
|
| Enzyme (CYP3A/ PgP inducers) |
|
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|
| Carbamazepine |
573 ± 168 mg/day |
3 mg twice daily |
0.51 |
0.55 |
Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors |
|
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|
|
| Ranitidine |
150 mg twice daily |
1 mg single dose |
1.2 |
1.4 |
Dose adjustment not needed |
| Cimetidine |
400 mg twice daily |
1 mg single dose |
1.1 |
1.3 |
Dose adjustment not needed |
| Erythromycin |
500 mg four times daily |
1 mg single dose |
1.1 |
0.94 |
Dose adjustment not needed |
| Other Drugs |
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| Amitriptyline |
50 mg twice daily |
3 mg twice daily |
1.2 |
1.1 |
Dose adjustment not needed |
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| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
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| CYP2C9 |
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast |
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 |
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton |
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 |
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton |
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
|
|
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| Anticoagulants |
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents |
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents |
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors |
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
| Drug/Drug Class (Mechanism of Interaction by the Drug) |
Voriconazole Plasma Exposure (Cmax and AUCτ after 200 mg q12h) |
Recommendations for Voriconazole Dosage Adjustment/Comments |
|---|---|---|
| Rifampin (CYP450 Induction) |
Significantly Reduced |
|
| Efavirenz (CYP450 Induction) |
Significantly Reduced | When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h |
| High-dose Ritonavir (400 mg q12h) |
Significantly Reduced |
|
| Low-dose Ritonavir (100 mg q12h) |
Reduced | Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole |
| Carbamazepine (CYP450 Induction) |
Not Studied |
|
| Long Acting Barbiturates (CYP450 Induction) |
Not Studied |
|
| Phenytoin (CYP450 Induction) |
Significantly Reduced | Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg) |
| St. John's Wort (CYP450 inducer; P-gp inducer) |
Significantly Reduced |
|
| Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition) |
Increased | Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives |
| Fluconazole |
Significantly Increased | Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole. |
| Other HIV Protease Inhibitors (CYP3A4 Inhibition) |
|
No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir |
|
|
Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors |
|
| Other NNRTIs (CYP3A4 Inhibition or CYP450 Induction) |
|
Frequent monitoring for adverse events and toxicity related to voriconazole |
| A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure) |
Careful assessment of voriconazole effectiveness |
| Drug/Drug Class (Mechanism of Interaction by Voriconazole) |
Drug Plasma Exposure (Cmax and AUCτ) |
Recommendations for Drug Dosage Adjustment/Comments |
|---|---|---|
| Sirolimus (CYP3A4 Inhibition) |
Significantly Increased |
|
| Rifabutin (CYP3A4 Inhibition) |
Significantly Increased |
|
| Efavirenz (CYP3A4 Inhibition) |
Significantly Increased | When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h |
| High-dose Ritonavir (400 mg q12h) |
No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ |
|
| Low-dose Ritonavir (100 mg q12h) |
Slight Decrease in Ritonavir Cmax and AUCτ | Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole |
| Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition) |
Not Studied |
|
| Ergot Alkaloids (CYP450 Inhibition) |
Not Studied |
|
| Cyclosporine (CYP3A4 Inhibition) |
AUCτ Significantly Increased; No Significant Effect on Cmax | When initiating therapy with VFEND in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary. |
| Methadone |
Increased | Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed |
| Fentanyl (CYP3A4 Inhibition) |
Increased | Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary [ |
| Alfentanil (CYP3A4 Inhibition) | Significantly Increased | Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [ |
| Oxycodone (CYP3A4 Inhibition) | Significantly Increased | Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary [ |
| NSAIDs (CYP2C9 Inhibition) |
Increased | Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [ |
| Tacrolimus (CYP3A4 Inhibition) |
Significantly Increased | When initiating therapy with VFEND in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary. |
| Phenytoin (CYP2C9 Inhibition) |
Significantly Increased | Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin. |
| Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition) |
Increased | Monitoring for adverse events related to oral contraceptives is recommended during coadministration. |
| Warfarin (CYP2C9 Inhibition) |
Prothrombin Time Significantly Increased | Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed. |
| Omeprazole (CYP2C19/3A4 Inhibition) |
Significantly Increased | When initiating therapy with VFEND in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors. |
| Other HIV Protease Inhibitors (CYP3A4 Inhibition) |
|
No dosage adjustment for indinavir when coadministered with VFEND |
|
(Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors | |
| Other NNRTIs (CYP3A4 Inhibition) |
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to NNRTI |
| Benzodiazepines (CYP3A4 Inhibition) |
(Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed. |
| HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition) |
(Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed. |
| Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition) |
(Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed. |
| Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition) |
Not Studied |
Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed. |
| Vinca Alkaloids (CYP3A4 Inhibition) |
Not Studied |
Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed. |
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| DRUG | DESCRIPTION OF INTERACTION |
| Sulfonylureas | Hypoglycemia potentiated. |
| Methotrexate | Decreases tubular reabsorption; clinical toxicity from methotrexate can result. |
| Oral Anticoagulants | Increased bleeding. |
| DRUG | DESCRIPTION OF INTERACTION |
| Corticosteroids | Decreases plasma salicylate level; tapering doses of steroids may promote salicylism. |
| Acidifying Agents | Increases plasma salicylate level. |
| Alkalizing Agents | Decreased plasma salicylate levels. |
| DRUG | DESCRIPTION OF INTERACTION |
| Heparin | Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients. |
| Pyrazinamide | Inhibits pyrazinamide-induced hyperuricemia. |
| Uricosuric Agents | Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited. |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
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| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
| AED Coadministered | AED Concentration | Topiramate Concentration |
| Phenytoin | NC or 25% increase |
48% decrease |
| Carbamazepine (CBZ) | NC | 40% decrease |
| CBZ epoxide |
NC | NE |
| Valproic acid | 11% decrease | 14% decrease |
| Phenobarbital | NC | NE |
| Primidone | NC | NE |
| Lamotrigine | NC at TPM doses up to 400 mg/day | 13% decrease |
| NC = Less than 10% change in plasma concentration. NE = Not Evaluated. |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
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| Amiodarone Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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| Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
|
|
|
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
| albuterol, systemic and inhaled | diltiazem | medroxyprogesterone | roxithromycin |
| dirithromycin | methylprednisolone | Sorbitol (purgative doses do not inhibit theophylline absorption) |
|
| amoxicillin | enflurane | metronidazole | |
| ampicillin, with or without sulbactam | famotidine | metoprolol | |
| felodipine | nadolol | ||
| finasteride | nifedipine | ||
| atenolol | hydrocortisone | nizatidine | sucralfate |
| azithromycin | isoflurane | norfloxacin | terbutaline, systemic |
| caffeine, dietary ingestion | isoniazid | ofloxacin | terfenadine |
| isradipine | omeprazole | tetracycline | |
| cefaclor | influenza vaccine | prednisone, prednisolone |
tocainide |
| co-trimoxazole (trimethoprim and sulfamethoxazole) | ketoconazole | ||
| lomefloxacin | ranitidine | ||
| mebendazole | rifabutin | ||
| * Refer to PRECAUTIONS, Drug Interactions for information regarding table. | |||
| AED Coadministered | Dose of AED (mg/day) |
Oxcarbazepine Dose (mg/day) |
Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval) | Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval) |
|---|---|---|---|---|
| Carbamazepine | 400-2000 | 900 | nc |
40% decrease [CI:17% decrease, 57% decrease] |
| Phenobarbital | 100-150 | 600-1800 | 14% increase [CI: 2% increase, 24% increase] |
25% decrease [CI:12% decrease, 51% decrease] |
| Phenytoin | 250-500 | 600-1800 >1200-2400 |
nc up to 40% increase [CI: 12% increase, 60% increase] |
30% decrease [CI: 3% decrease, 48% decrease] |
| Valproic acid | 400-2800 | 600-1800 | nc |
18% decrease [CI:13% decrease, 40% decrease] |
| Co-administered Drug | Dosing Schedule | Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (Ratio |
Risperidone Dose Recommendation | ||
| Co-administered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6) Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
|
|
|
|
|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
|
|
|
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
| Drug | Description of Interaction |
| Tolbutamide; Sulfonylureas | Hypoglycemia potentiated |
| Methotrexate | Decreases tubular reabsorption; clinical toxicity from methotrexate can result |
| Oral Anticoagulant | Increased bleeding |
| Drug | Description |
| Corticosteroids | Decreases plasma salicylate level; Tapering doses of steroids may promote salicylism |
| Ammonium Sulfate | Increases plasma salicylate level |
| Drug | Description |
| Heparin | Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients |
| Pyrazinamide | Inhibits pyrazinamide-induced hyperuricemia |
| Uricosuric Agents | Effect of probenecid, sulfinpyrazone and phenylbutazone inhibited |
| Laboratory Tests | Effect of Salicylates |
| Thyroid Function | Decreased PBI; increased T3 uptake |
| Urinary Sugar | False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5 g qd) |
| 5 Hydroxyindole acetic acid | False negative with fluorometric test |
| Acetone, Ketone Bodies | False positive FeCl3 in Gerhardt reaction; red color persists with boiling |
| 17-OH corticosteroids | False reduced values with >4.8 g qd salicylate |
| Vanilmandelic Acid | False reduced values |
| Uric Acid | May increase or decrease depending on dose |
| Prothrombin | Decreased levels; slightly increased prothrombin time |
|
|
|
| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine, danazol | Do not exceed 10 mg simvastatin daily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Diltiazem | Do not exceed 40 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
| Drug | Didanosine Dosage | n | AUC of Didanosine (90% CI) | Cmax of Didanosine (90% CI) |
|
|
400 mg single dose fasting 2 h before tenofovir | 26 |
(31, 67%) |
(25, 76%) |
|
|
400 mg single dose with tenofovir and a light meal | 25 |
(44, 79%) |
(41, 89%) |
|
|
|
|
(6, 27%)d |
(-25, 3%)d (-32, -7%)e (-24, 4%)e |
|
mL/min. b tenofovir disporoxil fumarate. c 373 kcalories, 8.2 grams fat. d Compared with didanosine delayed-release capsules 250 mg administered alone under fasting coniditions. e Compared with didanosine delayed-release capsules 400 mg administered alone under |
||||
| ↔ Indicates no change, or mean increase or decrease of less than 10%. | ||||
|
|
||||
|
|
|
|
|
|
|
750 mg single dose 800 mg single dose 200 mg single dose 300 mg once daily with a light meal 300 mg once daily with a light meal |
|
|
|
|
|
|
||||
| Drug | Didanosine Dosage | n | AUC Didanosine (95% CI) | Cmax of Didanosine (95% CI) |
|
|
200 mg single dose | 2 | ↑312% | ↑232% |
| healthy volunteer, 300 mg/day for 7 days | 400 mg single dose | 14 | ↑113% | ↑69% |
|
|
200 mg q12h | 12 | ↑111% | NA |
|
|
200 mg single dose | 16, 10a | ↓57% | ↓66% |
|
|
250c or 400 mg once daily for 7 days | 14 | ↑44% (31, 59%)d | ↔28% (11, 48%)d |
|
|
||||
| ciprofloxacin, 750 mg q12h for 3 days, 2 h before didanosine | 200 mg q12h for 3 days | 8e | ↓16% | ↓28% |
| ininavir, 800 mg single dose simultaneous | 200 mg single dose | 16 |
|
|
| 1 h before didanosine | 200 mg single dose | 16 | ↓17% (-27, -7%)d | ↓13% (-28, 5%)d |
| ketoconazole, 200 mg/day for 4 days, 2 h before didanosine | 375 mg q12h for 4 days | 12e | ↔ | ↓12% |
| loperamide, 4 mg q6h for 1 day | 300 mg single dose | 12e | ↔ | ↓23% |
| metoclopramide, 10 mg single dose | 300 mg single dose | 12e | ↔ | ↑13% |
| ranitidine, 150 mg 2 h before didansine | 375 mg single dose | 12e | ↑14% | ↑13% |
| rifabutin, 300 or 600 mg/day for 12 days | 167 or 250 mg q12h for 12 days | 11 | ↑13% (-1, 27%) | ↑17% (-4, 38%) |
| ritonavir, 600 mg q12h for 4 days | 200 mg q12h for 4 days | 12 | ↓13% (0, 23%) | ↓16% (5, 26%) |
| stavudine, 40 mg q12h for 4 days | 100 mg q12h for 4 days | 10 | ↔ | ↔ |
| sulfamethoxazole, 1000 mg single dose | 200 mg single dose | 8e | ↔ | ↔ |
| trimethoprim, 200 mg single dose | 200 mg single dose | 8e | ↔ | ↑17% (-23, 77%) |
| zidovudine, 200 mg q7h for 3 days | 200 mg q12h for 3 days | 8e | ↔ | ↔ |
|
↓ indicates decrease ↔ indicates no change, or mean increase or decrease of <10%. a Parellel-group design; entries are subjects receiving combination and control regimens, respectively. b tenogovir disoproxil fumarate c patients <60 kg with creatinine clearance >60 mL/min. e HIV-infected patients N/A Not available |
||||
| No Clinically Significant Interaction Observed | ||||
| Drug | Didanosine Dosage | n | AUC of Coadministered Drug (95% CI) | Cmax of Coadministered Drug (95% CI) |
| dapsone, 100 mg single dose | 200 mg q12h for 14 days | 6a | ↔ | ↔ |
| delaviridine, 400 mg single dose simultaneous | 125 or 200 mg q12h | 12a | ↓32%b | ↓53%b |
| 1 hr before didanosine | 125 or 200 mg q12h | 12a | ↑20% | ↑18% |
| ganciclovir, 1000 mg q8h, 2h after didanosine | 200 mg q12h | 12a | ↓21% | NA |
| nelfinavir, 750 mg single dose, 1 h after didanosine | 200 mg single dose | 10a | ↑12% | ↔ |
| ranitidine, 150 mg single dose, 2 h before didanosine | 375 mg single dose | 12a | ↓16% | ↔ |
| ritonavir, 600 mg q12h for 4 days | 200 mg q12h for 4 days | 12 | ↔ | ↔ |
| stavudine, 40 mg q12h for 4 days | 100 mg q12h for 4 days | 10a | ↔ | ↑17% |
| sulfamethoxazole, 1000 mg single dose | 200 mg single dose | 8a | ↓11% (-17, -4%) | ↓12% (-28, 8%) |
| tenofovir,C 300 mg once daily 1 h after didanosine | 250d or 400 mg once daily for 7 days | 14 | ↔ | ↔ |
| trimethoprim, 200 mg single dose | 200 mg single dose | 8a | ↑10% (-9, 34%) | ↓22% (-59, 49%) |
| zidovudine, 200 mg q8h for 3 days | 200 mg q12h for 3 days | 6a | ↓10% (-27, 11%) | ↓16.5% (-53, 47%) |
|
aHIV-infected patients. bThis result is probably related to the bugger and is not expected to occur with didanosine delayed-release capsules. ctenofovir disoproxil fumarate. dpatients <60 kg with creatinine clearance >60 mL/min. |
||||
| |
|
| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, Posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, gemfibrozil, cyclosporine,danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
| Coadministered Drug |
Dosing Schedule |
|
Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
|
Risperidone Dose Recommendation |
|
|
Coadministered Drug |
Risperidone |
AUC |
Cm
a
x
|
|
| Enzyme (CYP2D6) Inhibitors |
|
|
|
|
|
| Fluoxetine |
20 mg/day |
2 or 3 mg twice daily |
1.4 |
1.5 |
Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine |
10 mg/day |
4 mg/day |
1.3 |
- |
Re-evaluate dosing. |
|
|
20 mg/day |
4 mg/day |
1.6 |
- |
Do not exceed 8 mg/day |
|
|
40 mg/day |
4 mg/day |
1.8 |
- |
|
| Enzyme (CYP3A/ PgP inducers) |
|
|
|
|
|
| Carbamazepine |
573 ± 168 mg/day |
3 mg twice daily |
0.51 |
0.55 |
Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors |
|
|
|
|
|
| Ranitidine |
150 mg twice daily |
1 mg single dose |
1.2 |
1.4 |
Dose adjustment not needed |
| Cimetidine |
400 mg twice daily |
1 mg single dose |
1.1 |
1.3 |
Dose adjustment not needed |
| Erythromycin |
500 mg four times daily |
1 mg single dose |
1.1 |
0.94 |
Dose adjustment not needed |
| Other Drugs |
|
|
|
|
|
| Amitriptyline |
50 mg twice daily |
3 mg twice daily |
1.2 |
1.1 |
Dose adjustment not needed |
|
|
| *Refer to for information regarding table.
|
|||
| albuterol, systemic and inhaled | felodipinefinasteride | nizatidinenorfloxacin | |
| amoxicillin | hydrocortisone | ofloxacin | |
| ampicillin, with or without sulbactam | isoflurane isoniazid | omeprazole prednisone, prednisolone | |
| atenolol | isradipine | ranitidine | |
| azithromycin | influenza vaccine | rifabutin | |
| caffeine, dietary ingestion | ketoconazo lelomefloxacin | roxithromycin sorbitol | |
| cefaclor | mebendazole | (purgative doses do not | |
| co-trimoxazole (trimethoprim and sulfamethoxazole) | medroxyprogesteronemethylprednisolone | inhibit theophylline absorption) | |
| diltiazem | metronidazole | sucralfate | |
| dirithromycin | metoprolol | terbutaline, systemic | |
| enflurane | nadolol | terfenadine | |
| famotidine | nifedipine | tetracycline | |
| tocainide | |||
|
|
|
| Itraconazole, ketoconazole, Posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine,danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
|
|
|
|
|
Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
|
|
Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C Protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
|
Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide |
|
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels. | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate |
|
Increased lamotrigine concentrations slightly more than 2 fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
|
|
|
|
|---|---|---|
| Erythromycin (500 mg every 8 hrs) |
+82% | +109% |
| Ketoconazole (400 mg once daily) |
+135% | +164% |
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| Co-administered Drug | Dosing Schedule | Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (Ratio |
Risperidone Dose Recommendation | ||
| Co-administered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6) Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
|
|
||
| AED Co-administered |
AED Concentration |
Topiramate Concentration |
| Phenytoin |
NC or 25% increasea
|
48% decrease |
| Carbamazepine (CBZ) |
NC |
40% decrease |
| CBZ epoxideb
|
NC |
NE |
| Valproic acid |
11% decrease |
14% decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NC at TPM doses up to 400 mg/day |
13% decrease |
| Coadministered Drug | Dosing Schedule | Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio |
Risperidone Dose Recommendation | ||
|---|---|---|---|---|---|
| Coadministered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6) Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 mg twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/ PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient's usual dose |
| Enzyme (CYP3A) Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
|
|
|
| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine, danazol | Do not exceed 10 mg simvastatin daily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
|
Coadministered |
(mg/day) |
Dose (mg/day) |
Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval) |
AED on MHD Concentration (Mean Change, 90% Confidence Interval) |
| Carbamazepine | 400 to 2000 | 900 | nc1 | 40% decrease [CI: 17% decrease, 57% decrease] |
| Phenobarbital | 100 to 150 | 600 to 1800 | 14% increase [CI: 2% increase, 24% increase] |
25% decrease [CI: 12% decrease, 51% decrease] |
| Phenytoin | 250 to 500 | 600 to 1800 >1200 to 2400 |
nc1,2
up to 40% increase3 [CI: 12% increase, 60% increase] |
30% decrease [CI: 3% decrease, 48% decrease] |
| Valproic acid | 400 to 2800 | 600 to 1800 | nc1 | 18% decrease [CI: 13% decrease, 40% decrease] |
|
|
||
| AED Coadministered | AED Concentration | Topiramate Concentration |
| Phenytoin | NC or 25% increasea | 48% decrease |
| Carbamazepine (CBZ) | NC | 40% decrease |
| CBZ epoxideb | NC | NE |
| Valproic acid | 11% decrease | 14% decrease |
| Phenobarbital | NC | NE |
| Primidone | NC | NE |
| Lamotrigine | NC at TPM doses up to 400 mg/day | 15% increase |
| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
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|
| No fentanyl | 6.4 ± 0.0 | 6.3 ± 0.4 |
| 3 µg/kg fentanyl | 3.5 ± 1.9 (46%) | 3.1 ± 0.6 (51%) |
| 6 µg/kg fentanyl | 3.0 ± 1.2 (53%) | 2.3 ± 1.0 (64%) |
| No midazolam | 6.9 ± 0.1 | 5.9 ± 0.6 |
| 25 µg/kg midazolam | - | 4.9 ± 0.9 (16%) |
| 50 µg/kg midazolam | - | 4.9 ± 0.5 (17%) |
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| 0.65 MAC 60% N2O/O2 | 26 | 123 | - | - |
| 1.25 MAC 60% N2O/O2 | 18 | 91 | - | - |
| 1.25 MAC O2 | 22 | 120 | 362 | 19 |
| AED Coadministered |
AED Concentration |
Topiramate Concentration |
|
|
||
| Phenytoin |
NC or 25% increasea |
48% decrease |
| Carbamazepine (CBZ) |
NC |
40% decrease |
| CBZ epoxideb |
NC |
NE |
| Valproic acid |
11% decrease |
14% decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NC at TPM doses up to 400 mg/day |
13% decrease |
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) | Do not exceed 40 mg atorvastatin daily |
|
|
|
| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine, danazol | Do not exceed 10 mg simvastatin daily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
| blood dyscrasias - see cancer collagen vascular disease congestive heart failure |
diarrhea elevated temperature hepatic disorders infectious hepatitis jaundice |
hyperthyroidism poor nutritional state steatorrhea vitamin K deficiency |
| Classes of Drugs | |||
|---|---|---|---|
| 5-lipoxygenase Inhibitor Adrenergic Stimulants, Central Alcohol Abuse Reduction Preparations Analgesics Anesthetics, Inhalation Antiandrogen Antiarrhythmics† Antibiotics† Aminoglycosides (oral) Cephalosporins, parenteral Macrolides Miscellaneous Penicillins, intravenous, high dose Quinolones (fluoroquinolones) Sulfonamides, long acting Tetracyclines Anticoagulants Anticonvulsants† Antidepressants† Antimalarial Agents Antineoplastics† Antiparasitic/Antimicrobials |
Antiplatelet Drugs/Effects Antithyroid Drugs† Beta-Adrenergic Blockers Cholelitholytic Agents Diabetes Agents, Oral Diuretics† Fungal Medications, Intravaginal, Systemic† Gastric Acidity and Peptic Ulcer Agents† Gastrointestinal Prokinetic Agents Ulcerative Colitis Agents Gout Treatment Agents Hemorrheologic Agents Hepatotoxic Drugs Hyperglycemic Agents Hypertensive Emergency Agents Hypnotics† Hypolipidemics† Bile Acid-Binding Resins† Fibric Acid Derivatives HMG-CoA Reductase Inhibitors† |
Leukotriene Receptor Antagonist Monoamine Oxidase Inhibitors Narcotics, prolonged Nonsteroidal Anti- Inflammatory Agents Proton Pump Inhibitors Psychostimulants Pyrazolones Salicylates Selective Serotonin Reuptake Inhibitors Steroids, Adrenocortical† Steroids, Anabolic (17-Alkyl Testosterone Derivatives) Thrombolytics Thyroid Drugs Tuberculosis Agents† Uricosuric Agents Vaccines Vitamins† |
|
| Specific Drugs Reported | |||
|---|---|---|---|
| also: other medications affecting blood elements which may modify hemostasis dietary deficiencies prolonged hot weather unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported. |
|||
| acetaminophen alcohol† allopurinol aminosalicylic acid amiodarone HCl argatroban aspirin atenolol atorvastatin† azithromycin bivalirudin capecitabine cefamandole cefazolin cefoperazone cefotetan cefoxitin ceftriaxone celecoxib cerivastatin chenodiol chloramphenicol chloral hydrate† chlorpropamide cholestyramine† cimetidine ciprofloxacin cisapride clarithromycin clofibrate cyclophosphamide† danazol dextran dextrothyroxine diazoxide |
diclofenac dicumarol diflunisal disulfiram doxycycline erythromycin esomeprazole ethacrynic acid ezetimibe fenofibrate fenoprofen fluconazole fluorouracil fluoxetine flutamide fluvastatin fluvoxamine gefitinib gemifibrozil glucagon halothane heparin ibuprofen ifosfamide indomethacin influenza virus vaccine itraconazole ketoprofen ketorolac lansoprazole lepirudin levamisole levofloxacin levothyroxine liothyronine |
lovastatin mefenamic acid methimazole† methyldopa methylphenidate methylsalicylate ointment (topical) metronidazole miconazole (intravaginal, oral, systemic) moricizine hydrochloride† nalidixic acid naproxen neomycin norfloxacin ofloxacin olsalazine omeprazole oxandrolone oxaprozin oxymetholone pantoprazole paroxetine penicillin G, intravenous pentoxifylline phenylbutazone phenytoin† piperacillin piroxicam pravastatin† prednisone† propafenone |
propoxyphene propranolol propylthiouracil† quinidine quinine rabeprazole ranitidine† rofecoxib sertraline simvastatin stanozolol streptokinase sulfamethizole sulfamethoxazole sulfinpyrazone sulfisoxazole sulindac tamoxifen tetracycline thyroid ticarcillin ticlopidine tissue plasminogen activator (t-PA) tolbutamide tramadol trimethoprim/ sulfamethoxazole urokinase valdecoxib valproate vitamin E warfarin overdose zafirlukast zileuton |
| edema hereditary coumarin resistance hyperlipemia |
hypothyroidism nephrotic syndrome |
| Classes of Drugs | ||
|---|---|---|
| Adrenal Cortical Steroid Inhibitors Antacids Antianxiety Agents Antiarrhythmics† Antibiotics† Anticonvulsants† Antidepressants† Antihistamines Antineoplastics† |
Antipsychotic Medications Antithyroid Drugs† Barbiturates Diuretics† Enteral Nutritional Supplements Fungal Medications, Systemic† Gastric Acidity and Peptic Ulcer Agents† Hypnotics† |
Hypolipidemics† Bile Acid-Binding Resins† HMG-CoA Reductase Inhibitors† Immunosuppressives Oral Contraceptives, Estrogen Containing Selective Estrogen Receptor Modulators Steroids, Adrenocortical† Tuberculosis Agents† Vitamins† |
| Specific Drugs Reported | |||
|---|---|---|---|
| also: diet high in vitamin K unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported. |
|||
| alcohol† aminoglutethimide amobarbital atorvastatin† azathioprine butabarbital butalbital carbamazepine chloral hydrate† chlordiazepoxide chlorthalidone |
cholestyramine† clozapine corticotropin cortisone cyclophosphamide† dicloxacillin ethchlorvynol glutethimide griseofulvin haloperidol meprobamate |
6-mercaptopurine methimazole† moricizine hydrochloride† nafcillin paraldehyde pentobarbital phenobarbital phenytoin† pravastatin† prednisone† primidone |
propylthiouracil† raloxifene ranitidine† rifampin secobarbital spironolactone sucralfate trazodone vitamin C (high dose) vitamin K warfarin underdosage |
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) | Do not exceed 40 mg atorvastatin daily |
|
|
|
|
| Erythromycin (500 mg every 8 hrs) | +82% | +109% |
| Ketoconazole (400 mg once daily) | +135% | +164% |
| Concomitant Drug Class: Drug Name |
Effect on Concentration of Darunavir or Concomitant Drug | Clinical Comment |
|---|---|---|
|
|
||
| didanosine | ↔ darunavir ↔ didanosine |
Didanosine should be administered one hour before or two hours after PREZISTA/ritonavir (which are administered with food). |
|
|
||
| indinavir (The reference regimen for indinavir was indinavir/ritonavir 800/100 mg twice daily.) |
↑ darunavir ↑ indinavir |
The appropriate dose of indinavir in combination with PREZISTA/ritonavir has not been established. |
| lopinavir/ritonavir | ↓ darunavir ↔ lopinavir |
Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer lopinavir/ritonavir and PREZISTA, with or without ritonavir. |
| saquinavir | ↓ darunavir ↔ saquinavir |
Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer saquinavir and PREZISTA, with or without ritonavir. |
|
|
||
| maraviroc | ↑ maraviroc | Maraviroc concentrations are increased when co-administered with PREZISTA/ritonavir. When used in combination with PREZISTA/ritonavir, the dose of maraviroc should be 150 mg twice daily. |
|
|
||
|
bepridil, lidocaine (systemic), quinidine, amiodarone, flecainide, propafenone |
↑ antiarrhythmics | Concentrations of these drugs may be increased when co-administered with PREZISTA/ritonavir. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when co-administered with PREZISTA/ritonavir. |
| digoxin | ↑ digoxin | The lowest dose of digoxin should initially be prescribed. The serum digoxin concentrations should be monitored and used for titration of digoxin dose to obtain the desired clinical effect. |
|
warfarin |
↓ warfarin ↔ darunavir |
Warfarin concentrations are decreased when co-administered with PREZISTA/ritonavir. It is recommended that the international normalized ratio (INR) be monitored when warfarin is combined with PREZISTA/ritonavir. |
|
carbamazepine |
↔ darunavir ↑ carbamazepine |
The dose of either darunavir/ritonavir or carbamazepine does not need to be adjusted when initiating co-administration with darunavir/ritonavir and carbamazepine. Clinical monitoring of carbamazepine concentrations and its dose titration is recommended to achieve the desired clinical response. |
|
phenobarbital, phenytoin |
↔ darunavir ↓ phenytoin ↓ phenobarbital |
Co-administration of PREZISTA/ritonavir may cause a decrease in the steady-state concentrations of phenytoin and phenobarbital. Phenytoin and phenobarbital levels should be monitored when co-administering with PREZISTA/ritonavir. |
|
trazodone, desipramine |
↑ trazodone ↑ desipramine |
Concomitant use of trazodone or desipramine and PREZISTA/ritonavir may increase plasma concentrations of trazodone or desipramine which may lead to adverse events such as nausea, dizziness, hypotension and syncope. If trazodone or desipramine is used with PREZISTA/ritonavir, the combination should be used with caution, and a lower dose of trazodone or desipramine should be considered. |
|
clarithromycin |
↔ darunavir ↑ clarithromycin |
No dose adjustment of the combination is required for patients with normal renal function. For patients with renal impairment, the following dose adjustments should be considered:
|
|
ketoconazole, itraconazole, voriconazole |
↑ ketoconazole ↑ darunavir ↑ itraconazole (not studied) ↓ voriconazole (not studied) |
Ketoconazole and itraconazole are potent inhibitors as well as substrates of CYP3A. Concomitant systemic use of ketoconazole, itraconazole, and darunavir/ritonavir may increase plasma concentration of darunavir. |
| Plasma concentrations of ketoconazole or itraconazole may be increased in the presence of darunavir/ritonavir. When co-administration is required, the daily dose of ketoconazole or itraconazole should not exceed 200 mg. | ||
| Plasma concentrations of voriconazole may be decreased in the presence of darunavir/ritonavir. Voriconazole should not be administered to patients receiving darunavir/ritonavir unless an assessment of the benefit/risk ratio justifies the use of voriconazole. | ||
|
colchicine |
↑ colchicine |
0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days. If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Patients with renal or hepatic impairment should not be given colchicine with PREZISTA/ritonavir. |
|
artemether/lumefantrine |
↓ artemether ↓ dihydroartemisinin ↑ lumefantrine ↔ darunavir |
The combination of PREZISTA and artemether/lumefantrine can be used without dose adjustments. However, the combination should be used with caution as increased lumefantrine exposure may increase the risk of QT prolongation. |
|
rifabutin |
↑ darunavir ↑ rifabutin ↑ 25- |
Dose reduction of rifabutin by at least 75% of the usual dose (300 mg once daily) is recommended (i.e., a maximum dose of 150 mg every other day). Increased monitoring for adverse events is warranted in patients receiving this combination and further dose reduction of rifabutin may be necessary. |
| The reference regimen for rifabutin was 300 mg once daily | ||
|
metoprolol, timolol |
↑ beta-blockers | Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir. |
|
parenterally administered midazolam |
↑ midazolam | Concomitant use of parenteral midazolam with PREZISTA/ritonavir may increase plasma concentrations of midazolam. Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Co-administration of oral midazolam with PREZISTA/ritonavir is CONTRAINDICATED. |
|
felodipine, nifedipine, nicardipine |
↑ calcium channel blockers | Plasma concentrations of calcium channel blockers (e.g., felodipine, nifedipine, nicardipine) may increase when PREZISTA/ritonavir are co-administered. Caution is warranted and clinical monitoring of patients is recommended. |
|
dexamethasone |
↓ darunavir | Systemic dexamethasone induces CYP3A and can thereby decrease darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA. |
|
fluticasone |
↑ fluticasone | Concomitant use of inhaled fluticasone and PREZISTA/ritonavir may increase plasma concentrations of fluticasone. Alternatives should be considered, particularly for long-term use. |
|
bosentan |
↑ bosentan |
In patients who have been receiving PREZISTA/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of PREZISTA/ritonavir. After at least 10 days following the initiation of PREZISTA/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. |
|
NS3-4A protease inhibitors: boceprevir telaprevir |
↓ darunavir ↓ boceprevir ↓ telaprevir |
|
|
pravastatin, atorvastatin, rosuvastatin |
↑ pravastatin ↑ atorvastatin ↑ rosuvastatin |
Titrate atorvastatin, pravastatin or rosuvastatin dose carefully and use the lowest necessary dose while monitoring for safety. Do not exceed atorvastatin 20 mg/day. |
|
cyclosporine, tacrolimus, sirolimus |
↑ immunosuppressants | Plasma concentrations of cyclosporine, tacrolimus or sirolimus may be increased when co-administered with PREZISTA/ritonavir. Therapeutic concentration monitoring of the immunosuppressive agent is recommended when co-administered with PREZISTA/ritonavir. |
|
salmeterol |
↑ salmeterol | Concurrent administration of salmeterol and PREZISTA/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
|
methadone, buprenorphine, buprenorphine/naloxone |
↓ methadone ↔ buprenorphine, naloxone ↑ norbuprenorphine (metabolite) |
No adjustment of methadone dosage is required when initiating co-administration of PREZISTA/ritonavir. However, clinical monitoring is recommended as the dose of methadone during maintenance therapy may need to be adjusted in some patients. No dose adjustment for buprenorphine or buprenorphine/naloxone is required with concurrent administration of PREZISTA/ritonavir. Clinical monitoring is recommended if PREZISTA/ritonavir and buprenorphine or buprenorphine/naloxone are coadministered. |
|
risperidone, thioridazine |
↑ neuroleptics | A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir. |
|
ethinyl estradiol, norethindrone |
↓ ethinyl estradiol ↓ norethindrone |
Plasma concentrations of ethinyl estradiol are decreased due to induction of its metabolism by ritonavir. Alternative methods of nonhormonal contraception are recommended. |
|
sildenafil, vardenafil, tadalafil |
↑ PDE-5 inhibitors (only the use of sildenafil at doses used for treatment of erectile dysfunction has been studied with PREZISTA/ritonavir) |
Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg dose in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours can be used with increased monitoring for PDE-5 inhibitor-associated adverse events. |
|
sertraline, paroxetine |
↔ darunavir ↓ sertraline ↓ paroxetine |
If sertraline or paroxetine is co-administered with PREZISTA/ritonavir, the recommended approach is a careful dose titration of the SSRI based on a clinical assessment of antidepressant response. In addition, patients on a stable dose of sertraline or paroxetine who start treatment with PREZISTA/ritonavir should be monitored for antidepressant response. |
| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of this product. |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding |
| Antidiabetic agents |
Carefully monitor blood glucose |
|
|
|
| Tolbutamide; Sulfonylureas | Hypoglycemia potentiated |
| Methotrexate | Decreases tubular reabsorption; clinical toxicity from methotrexate can result |
| Oral Anticoagulant | Increased bleeding |
|
|
|
| Corticosteroids | Decreases plasma salicylate level; Tapering doses of steroids may promote salicylism |
| Ammonium Sulfate | Increases plasma salicylate level |
|
|
|
| Heparin | Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients |
| Pyrazinamide | Inhibits pyrazinamide-induced hyperuricemia |
| Uricosuric Agents | Effect of probenecid, sulfinpyrazone and phenylbutazone inhibited |
|
|
|
| Thyroid Function | Decreased PBI; increased T3 uptake |
| Urinary Sugar | False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5 g qd) |
| 5 Hydroxyindole acetic acid | False negative with fluorometric test |
| Acetone, Ketone Bodies | False positive FeCl3 in Gerhardt reaction; red color persists with boiling |
| 17-OH corticosteroids | False reduced values with >4.8 g qd salicylate |
| Vanilmandelic Acid | False reduced values |
| Uric Acid | May increase or decrease depending on dose |
| Prothrombin | Decreased levels; slightly increased prothrombin time |
|
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|
|
| Dopamine / Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day). |
|
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|
|
| Aminoglutethimide Amiodarone Iodide(including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
|
|
|
| Amiodarone Iodide(including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
|
|
|
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
|
|
|
|
|
|
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
| Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4, and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
|
|
|
|
|
|
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
|
|
|
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
|
|
|
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms. |
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| Atazanavir/Ritonavir* | ↓ Atazanavir ↑ Nevirapine |
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures. |
| Fosamprenavir* | ↓Amprenavir ↑Nevirapine |
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. |
| Fosamprenavir/Ritonavir* | ↓Amprenavir ↑Nevirapine |
No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied. |
| Indinavir* | ↓ Indinavir | The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established. |
| Lopinavir/Ritonavir* | ↓Lopinavir | Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. |
| Nelfinavir* | ↓Nelfinavir M8 Metabolite ↓Nelfinavir Cmin |
The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established. |
| Saquinavir/ritonavir | The interaction between nevirapine and saquinavir/ritonavir has not been evaluated | The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established. |
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| Efavirenz* | ↓ Efavirenz |
The appropriate doses of these combinations with respect to safety and efficacy have not been established. |
|
Delavirdine Etravirine Rilpivirine |
Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial. |
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|
Methadone* |
↓ Methadone |
Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. |
|
Amiodarone, disopyramide, lidocaine |
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
|
Clarithromycin* |
↓ Clarithromycin ↑ 14-OH clarithromycin |
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against |
| Rifabutin* |
↑Rifabutin |
Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. |
| Rifampin* |
↓ Nevirapine |
Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead. |
|
Carbamazepine, clonazepam, ethosuximide |
Plasma concentrations of nevirapine and the anticonvulsant may be decreased. |
Use with caution and monitor virologic response and levels of anticonvulsants. |
|
Fluconazole* |
↑Nevirapine |
Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events. |
| Ketoconazole* |
↓ Ketoconazole |
Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. |
| Itraconazole |
↓ Itraconazole |
Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug. |
|
Warfarin |
Plasma concentrations may be decreased. | Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended. |
|
Diltiazem, nifedipine, verapamil |
Plasma concentrations may be decreased. | Appropriate doses for these combinations have not been established. |
|
Cyclophosphamide |
Plasma concentrations may be increased. | Appropriate doses for this combination have not been established. |
|
Ergotamine |
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
|
Cyclosporine, tacrolimus, sirolimus |
Plasma concentrations may be decreased. | Appropriate doses for these combinations have not been established. |
|
Cisapride |
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
|
Fentanyl |
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. |
|
Ethinyl estradiol and Norethindrone* |
↓ Ethinyl estradiol ↓ Norethindrone |
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended. |
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| HIV-1 Protease Inhibitor: fosamprenavir/ritonavir |
↓ amprenavir ↓ lopinavir |
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor: indinavir* |
↑ indinavir | Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily |
| HIV-1 Protease Inhibitor: nelfinavir* |
↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir |
KALETRA should not be administered once daily in combination with nelfinavir |
| HIV-1 Protease Inhibitor: ritonavir* |
↑ lopinavir | Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor: saquinavir* |
↑ saquinavir | The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir. |
| HIV-1 Protease Inhibitor: tipranavir |
↓ lopinavir AUC and Cmin | KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily). |
| HIV CCR5 – Antagonist: maraviroc |
↑ maraviroc | Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry® (maraviroc). |
| Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz*, nevirapine* |
↓ lopinavir | KALETRA dose increase is recommended in all patients Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz. KALETRA should not be administered once daily in combination with efavirenz or nevirapine |
| Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine |
↑ lopinavir | Appropriate doses of the combination with respect to safety and efficacy have not been established. |
| Nucleoside Reverse Transcriptase Inhibitor: didanosine |
KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food). |
|
| Nucleoside Reverse Transcriptase Inhibitor: tenofovir |
↑ tenofovir | KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir. |
| Nucleoside Reverse Transcriptase Inhibitors: abacavir zidovudine |
↓ abacavir ↓ zidovudine |
KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown. |
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| Antiarrhythmics e.g.: amiodarone, bepridil, lidocaine (systemic), quinidine |
↑ antiarrhythmics | Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA. |
| Anticancer Agents: vincristine, vinblastine, dasatinib, nilotinib |
↑ anticancer agents | Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents. For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions. |
| Anticoagulants: warfarin, rivaroxaban |
↑ rivaroxaban | Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored. Avoid concomitant use of rivaroxaban and KALETRA. Co-administration of KALETRA and rivaroxaban is expected to result in increased exposure of rivaroxaban which may lead to risk of increased bleeding. |
| Anticonvulsants: carbamazepine, phenobarbital, phenytoin |
↓ lopinavir ↓ phenytoin |
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA. |
| Anticonvulsants: lamotrigine, valproate |
↓ lamotrigine ↓ or ↔ valproate |
Co-administration of KALETRA and lamotrigine or valproate may decrease the exposure of lamotrigine or valproate. A dose increase of lamotrigine or valproate may be needed when co-administered with KALETRA and therapeutic concentration monitoring for lamotrigine may be indicated; particularly during dosage adjustments |
| Antidepressant: bupropion |
↓ bupropion ↓ active metabolite, hydroxybupropion |
Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion. |
| Antidepressant: trazodone |
↑ trazodone | Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered. |
| Anti-infective: clarithromycin |
↑ clarithromycin | For patients with renal impairment, the following dosage adjustments should be considered: • For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. • For patients with CLCR < 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary. |
| Antifungals: ketoconazole*, itraconazole, voriconazole |
↑ ketoconazole ↑ itraconazole ↓ voriconazole |
High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended. Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients. |
| Anti-gout: colchicine |
↑ colchicine | Patients with renal or hepatic impairment should not be given colchicine with KALETRA. 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). |
| Antimycobacterial: rifabutin* |
↑ rifabutin and rifabutin metabolite | Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary. |
| Antimycobacterial: rifampin |
↓ lopinavir | May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone |
| Antiparasitic: atovaquone |
↓ atovaquone | Clinical significance is unknown; however, increase in atovaquone doses may be needed. |
| Benzodiazepines: parenterally administered midazolam | ↑ midazolam | Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam |
| Contraceptive: ethinyl estradiol* |
↓ ethinyl estradiol | Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended. |
| Corticosteroids (systemic): e.g. budesonide, dexamethasone, prednisone |
↓ lopinavir ↑ glucocorticoids |
Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly. Concomitant use may result in increased steroid concentrations and reduced serum cortisol concentrations. Concomitant use of glucocorticoids that are metabolized by CYP3A, particularly for long-term use, should consider the potential benefit of treatment versus the risk of systemic corticosteroid effects. Concomitant use may increase the risk for development of systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression. |
| Dihydropyridine Calcium Channel Blockers: e.g. felodipine, nifedipine, nicardipine |
↑ dihydropyridine calcium channel blockers | Caution is warranted and clinical monitoring of patients is recommended. |
| Disulfiram/metronidazole | KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole). | |
| Endothelin Receptor Antagonists: bosentan |
↑ bosentan |
In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. |
| HCV-Protease Inhibitor: boceprevir |
↓ lopinavir ↓ boceprevir ↓ ritonavir |
It is not recommended to co-administer KALETRA and boceprevir. Concomitant administration of KALETRA and boceprevir reduced boceprevir, lopinavir and ritonavir steady-state exposures |
| HCV-Protease Inhibitor: telaprevir |
↓ telaprevir ↔ lopinavir |
It is not recommended to co-administer KALETRA and telaprevir. Concomitant administration of KALETRA and telaprevir reduced steady-state telaprevir exposure, while the steady-state lopinavir exposure was not affected |
| HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin |
↑ atorvastatin ↑ rosuvastatin |
Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day. See Drugs with No Observed or Predicted Interactions with KALETRA |
| Immunosuppressants: e.g. cyclosporine, tacrolimus, sirolimus |
↑ immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA. |
| Inhaled or Intranasal Steroids e.g.: fluticasone, budesonide |
↑ glucocorticoids | Concomitant use of KALETRA and fluticasone or other glucocorticoids that are metabolized by CYP3A is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. Concomitant use may result in increased steroid concentrations and reduce serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during postmarketing use in patients when certain ritonavir-containing products have been co-administered with fluticasone propionate or budesonide. |
| Long-acting beta-adrenoceptor Agonist: salmeterol |
↑ salmeterol | Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
| Narcotic Analgesics: methadone,* fentanyl |
↓ methadone ↑ fentanyl |
Dosage of methadone may need to be increased when co-administered with KALETRA. Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA. |
| PDE5 inhibitors: avanafil, sildenafil, tadalafil, vardenafil |
↑ avanafil ↑ sildenafil ↑ tadalafil ↑ vardenafil |
Do not use KALETRA with avanafil because a safe and effective avanafil dosage regimen has not been established. Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA The following dose adjustments are recommended for use of tadalafil (Adcirca®) with KALETRA: In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: It is recommended not to exceed the following doses: • Sildenafil: 25 mg every 48 hours • Tadalafil: 10 mg every 72 hours • Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events. |
| * |
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|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
| ↑ Indicates increase. ↓ Indicates decrease. |
||
| Drug | Effect | Clinical Comment |
| ganciclovir | ↑didanosine concentration | If there is no suitable alternative to ganciclovir, then use in combination with didanosine delayed-release capsules with caution. Monitor for didanosine-associated toxicity. |
| methadone | ↓didanosine concentration | If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is didanosine delayed-release capsules. Patients should be closely monitored for adequate clinical response when didanosine delayed-release capsules are coadministered with methadone, including monitoring for changes in HIV RNA viral load. Do not coadminister methadone with didanosine pediatric powder due to significant decreases in didanosine concentrations. |
| nelfinavir | No interaction 1 hour after didanosine | Administer nelfinavir 1 hour after didanosine delayed-release capsules. |
|
|
↑didanosine concentration |
|
| ↑ Indicates increase. | ||
|
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|
| Drugs that may cause pancreatic toxicity | ↑risk of pancreatitis | Use only with extreme caution. |
| Neurotoxic drugs | ↑risk of neuropathy | Use with caution. |
| Interacting Drug | Interaction |
| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of this product. |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding |
| Antidiabetic agents |
Carefully monitor blood glucose |
|
|
|
(mg) |
|
Pharmacokinetic Parameters (90% CI); No Effect = 1.00 |
||
| Cmax | AUC | Cmin | ||||
| All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated. | ||||||
| Cimetidine | 600 twice daily, 6 days |
400 single dose | 12 | 1.07 (0.77, 1.49) |
0.98 (0.81, 1.19) |
0.82 (0.69, 0.99) |
| Clarithromycin | 500 q12h, 7 days |
800 three times daily, 7 days |
10 | 1.08 (0.85, 1.38) |
1.19 (1.00, 1.42) |
1.57 (1.16, 2.12) |
| Delavirdine | 400 three times daily | 400 three times daily, 7 days |
28 | 0.64 (0.48, 0.86) |
No significant change |
2.18 (1.16, 4.12) |
| Delavirdine | 400 three times daily | 600 three times daily, 7 days |
28 | No significant change | 1.53 (1.07, 2.20) |
3.98 (2.04, 7.78) |
| Efavirenz |
600 once daily, 10 days |
1000 three times daily, 10 days |
20 | |||
| After morning dose | No significant change |
0.67 (0.61, 0.74) |
0.61 (0.49, 0.76) |
|||
| After afternoon dose | No significant change |
0.63 (0.54, 0.74) |
0.48 (0.43, 0.53) |
|||
| After evening dose | 0.71 (0.57, 0.89) |
0.54 (0.46, 0.63) |
0.43 (0.37, 0.50) |
|||
| Fluconazole |
400 once daily, 8 days |
1000 three times daily, 7 days | 11 | 0.87 (0.72, 1.05) |
0.76 (0.59, 0.98) |
0.90 (0.72, 1.12) |
| Grapefruit Juice | 8 oz. | 400 single dose | 10 | 0.65 (0.53, 0.79) |
0.73 (0.60, 0.87) |
0.90 (0.71, 1.15) |
| Isoniazid | 300 once daily in the morning, 8 days |
800 three times daily, 7 days | 11 | 0.95 (0.88, 1.03) |
0.99 (0.87, 1.13) |
0.89 (0.75, 1.06) |
| Itraconazole | 200 twice daily, 7 days |
600 three times daily, 7 days |
12 | 0.78 (0.69, 0.88) |
0.99 (0.91, 1.06) |
1.49 (1.28, 1.74) |
| Ketoconazole | 400 once daily, 7 days |
600 three times daily, 7 days |
12 | 0.69 (0.61, 0.78) |
0.80 (0.74, 0.87) |
1.29 (1.11, 1.51) |
| 400 once daily, 7 days |
400 three times daily, 7 days |
12 | 0.42 (0.37, 0.47) |
0.44 (0.41, 0.48) |
0.73 (0.62, 0.85) |
|
| Methadone | 20-60 once daily in the morning, 8 days |
800 three times daily, 8 days |
10 | See text below for discussion of interaction. | ||
| Quinidine | 200 single dose | 400 single dose | 10 | 0.96 (0.79, 1.18) |
1.07 (0.89, 1.28) |
0.93 (0.73, 1.19) |
| Rifabutin | 150 once daily in the morning, 10 days |
800 three times daily, 10 days |
14 | 0.80 (0.72, 0.89) |
0.68 (0.60, 0.76) |
0.60 (0.51, 0.72) |
| Rifabutin | 300 once daily in the morning, 10 days |
800 three times daily, 10 days |
10 | 0.75 (0.61, 0.91) |
0.66 (0.56, 0.77) |
0.61 (0.50, 0.75) |
| Rifampin | 600 once daily in the morning, 8 days |
800 three times daily, 7 days |
12 | 0.13 (0.08, 0.22) |
0.08 (0.06, 0.11) |
Not Done |
| Ritonavir | 100 twice daily, 14 days |
800 twice daily, 14 days |
10, 16 |
See text below for discussion of interaction. | ||
| Ritonavir | 200 twice daily, 14 days |
800 twice daily,14 days |
9, 16 |
See text below for discussion of interaction. | ||
| Sildenafil | 25 single dose | 800 three times daily | 6 | See text below for discussion of interaction. | ||
| St. John's wort ( standardized to 0.3 % hypericin) |
300 three times daily with meals, 14 days |
800 three times daily | 8 | Not Available | 0.46 (0.34, 0.58) |
0.19 (0.06, 0.33) |
| Stavudine (d4T) |
40 twice daily, 7 days |
800 three times daily, 7 days |
11 | 0.95 (0.80, 1.11) |
0.95 (0.80, 1.12) |
1.13 (0.83, 1.53) |
| Trimethoprim/ Sulfamethoxazole |
800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days |
400 four times daily, 7 days |
12 | 1.12 (0.87, 1.46) |
0.98 (0.81, 1.18) |
0.83 (0.72, 0.95) |
| Zidovudine |
200 three times daily, 7 days | 1000 three times daily, 7 days |
12 | 1.06 (0.91, 1.25) |
1.05 (0.86, 1.28) |
1.02 (0.77, 1.35) |
| Zidovudine/ Lamivudine (3TC) |
200/150 three times daily, 7 days | 800 three times daily, 7 days |
6, 9 |
1.05 (0.83, 1.33) |
1.04 (0.67, 1.61) |
0.98 (0.56, 1.73) |
|
|
|
|
|
Pharmacokinetic Parameters (90% CI); No Effect = 1.00 |
||
| Cmax | AUC | Cmin | ||||
| All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated. | ||||||
| Clarithromycin | 500 twice daily, 7 days |
800 three times daily, 7 days | 12 | 1.19 (1.02, 1.39) |
1.47 (1.30, 1.65) |
1.97 (1.58, 2.46) n=11 |
| Efavirenz | 200 once daily, 14 days |
800 three times daily, 14 days | 20 | No significant change | No significant change | -- |
| Ethinyl Estradiol (ORTHO-NOVUM 1/35) |
35 mcg, 8 days | 800 three times daily, 8 days | 18 | 1.02 (0.96, 1.09) |
1.22 (1.15, 1.30) |
1.37 (1.24, 1.51) |
| Isoniazid | 300 once daily in the morning, 8 days |
800 three times daily, 8 days | 11 | 1.34 (1.12, 1.60) |
1.12 (1.03, 1.22) |
1.00 (0.92, 1.08) |
| Methadone |
20-60 once daily in the morning, 8 days |
800 three times daily, 8 days | 12 | 0.93 (0.84, 1.03) |
0.96 (0.86, 1.06) |
1.06 (0.94, 1.19) |
| Norethindrone (ORTHO-NOVUM 1/35) |
1 mcg, 8 days | 800 three times daily, 8 days | 18 | 1.05 (0.95, 1.16) |
1.26 (1.20, 1.31) |
1.44 (1.32, 1.57) |
| Rifabutin 150 mg once daily in the morning, 11 days + indinavir compared to 300 mg once daily in the morning, 11 days alone |
150 once daily in the morning, 10 days 300 once daily in the morning, 10 days |
800 three times daily, 10 days 800 three times daily, 10 days |
14 10 |
1.29 (1.05, 1.59) 2.34 (1.64, 3.35) |
1.54 (1.33, 1.79) 2.73 (1.99, 3.77) |
1.99 (1.71, 2.31) n=13 3.44 (2.65, 4.46) n=9 |
| Ritonavir | 100 twice daily, 14 days |
800 twice daily, 14 days |
10, 4 |
1.61 (1.13, 2.29) |
1.72 (1.20, 2.48) |
1.62 (0.93, 2.85) |
| 200 twice daily, 14 days |
800 twice daily, 14 days |
9, 5 |
1.19 (0.85, 1.66) |
1.96 (1.39, 2.76) |
4.71 (2.66, 8.33) n=9, 4 |
|
| Saquinavir | ||||||
| Hard gel formulation | 600 single dose | 800 three times daily, 2 days | 6 | 4.7 (2.7, 8.1) |
6.0 (4.0, 9.1) |
2.9 (1.7, 4.7) |
| Soft gel formulation | 800 single dose | 800 three times daily, 2 days | 6 | 6.5 (4.7, 9.1) |
7.2 (4.3, 11.9) |
5.5 (2.2, 14.1) |
| Soft gel formulation | 1200 single dose | 800 three times daily, 2 days | 6 | 4.0 (2.7, 5.9) |
4.6 (3.2, 6.7) |
5.5 (3.7, 8.3) |
| Sildenafil | 25 single dose | 800 three times daily | 6 | See text below for discussion of interaction. | ||
| Stavudine |
40 twice daily, 7 days |
800 three times daily, 7 days | 13 | 0.86 (0.73, 1.03) |
1.21 (1.09, 1.33) |
Not Done |
| Theophylline | 250 single dose (on Days 1 and 7) | 800 three times daily, 6 days (Days 2 to 7) | 12, 4 |
0.88 (0.76, 1.03) |
1.14 (1.04, 1.24) |
1.13 (0.86, 1.49) n=7, 3 |
| Trimethoprim/ Sulfamethoxazole |
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| Trimethoprim | 800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days |
400 q6h, 7 days | 12 | 1.18 (1.05, 1.32) |
1.18 (1.05, 1.33) |
1.18 (1.00, 1.39) |
| Trimethoprim/ Sulfamethoxazole |
||||||
| Sulfamethoxazole | 800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days |
400 q6h, 7 days | 12 | 1.01 (0.95, 1.08) |
1.05 (1.01, 1.09) |
1.05 (0.97, 1.14) |
| Vardenafil | 10 single dose | 800 three times daily | 18 | See text below for discussion of interaction. | ||
| Zidovudine |
200 three times daily, 7 days | 1000 three times daily, 7 days | 12 | 0.89 (0.73, 1.09) |
1.17 (1.07, 1.29) |
1.51 (0.71, 3.20) n=4 |
| Zidovudine/ Lamivudine |
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| Zidovudine | 200/150 three times daily, 7 days | 800 three times daily, 7 days | 6, 7 |
1.23 (0.74, 2.03) |
1.39 (1.02, 1.89) |
1.08 (0.77, 1.50) n=5, 5 |
| Zidovudine/ Lamivudine |
||||||
| Lamivudine | 200/150 three times daily, 7 days | 800 three times daily, 7 days | 6, 7 |
0.73 (0.52, 1.02) |
0.91 (0.66, 1.26) |
0.88 (0.59, 1.33) |
|
Drug Name |
Concentration |
|
|---|---|---|
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| Delavirdine | ↑ nelfinavir (Cmin) ↓ delavirdine |
Concentrations of nelfinavir were increased while concentrations of delavirdine were decreased when the two agents were coadministered. Appropriate doses of the combination, with respect to safety and efficacy, have not been established. |
| Nevirapine | ↓ nelfinavir (Cmin) | Concentrations of nelfinavir were decreased when coadministered with nevirapine. An appropriate dose of nelfinavir with respect to safety and efficacy has not been established. |
| Didanosine | ↔ nelfinavir | There was no change in nelfinavir concentration when coadministered with didanosine. However, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after VIRACEPT (given with food). |
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| Indinavir | ↑ nelfinavir ↑ indinavir |
Concentrations of both indinavir and nelfinavir were increased when the two agents were coadministered. Appropriate doses for these combinations, with respect to safety and efficacy, have not been established. |
| Ritonavir | ↑ nelfinavir ↔ ritonavir |
Concentrations of nelfinavir were increased when coadministered with ritonavir. An appropriate dose of nelfinavir for this combination, with respect to safety and efficacy, has not been established. |
| Saquinavir | ↑ nelfinavir ↑ saquinavir |
Concentrations of both saquinavir and nelfinavir were increased when the two agents were coadministered. Appropriate doses for these combinations, with respect to safety and efficacy, have not been established. |
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| Warfarin | Warfarin | Coadministration of warfarin and VIRACEPT may affect concentrations of warfarin. It is recommended that the INR (international normalized ratio) be monitored carefully during treatment with VIRACEPT, especially when commencing therapy. |
|
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| Carbamazepine Phenobarbital Phenytoin |
↓ nelfinavir ↓ phenytoin |
Concentrations of nelfinavir may be decreased. VIRACEPT may not be effective due to decreased nelfinavir plasma concentrations in patients taking these agents concomitantly. Phenytoin plasma/serum concentrations should be monitored; phenytoin dose may require adjustment to compensate for altered phenytoin concentration. |
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| Trazodone | ↑ trazodone | Concomitant use of trazodone and VIRACEPT may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as VIRACEPT, the combination should be used with caution and a lower dose of trazodone should be considered. |
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| Colchicine | ↑ colchicines | Patients with renal or hepatic impairment should not be given colchicine with VIRACEPT due to the risk of colchicine toxicity. Treatment of gout flares – co- administration of colchicine in patients on VIRACEPT: 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout-flares – coadministration of colchicine in patients on VIRACEPT: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF)– coadministration of colchicine in patients on VIRACEPT: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). |
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| Rifabutin | ↑ rifabutin ↓ nelfinavir (750 mg TID) ↔ nelfinavir (1250 mg BID) |
It is recommended that the dose of rifabutin be reduced to one-half the usual dose when administered with VIRACEPT; 1250 mg BID is the preferred dose of VIRACEPT when coadministered with rifabutin. |
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| Bosentan | ↑ bosentan | Concentrations of bosentan may be increased when coadministered with VIRACEPT. Coadministration of bosentan in patients on VIRACEPT or coadministration of VIRACEPT in patients on bosentan: Start at or adjust bosentan to 62.5 mg once daily or every other day based upon individual tolerability. |
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| Atorvastatin Rosuvastatin |
↑ atorvastatin ↑ rosuvastatin |
Titrate atorvastatin dose carefully and use the lowest necessary dose; do not exceed atorvastatin 40 mg/day. |
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| Cyclosporine Tacrolimus Sirolimus |
↑ immuno-suppressants ↑ nelfinavir |
Concentrations of these immunosuppressants and nelfinavir may be increased by coadministration of these agents with nelfinavir. |
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| Salmeterol | ↑ salmeterol | Concurrent administration of salmeterol with VIRACEPT is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
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| Fluticasone | ↑ fluticasone | Concomitant use of fluticasone propionate and VIRACEPT may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use. |
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| Azithromycin | ↑ azithromycin | Dose adjustment of azithromycin is not recommended, but close monitoring for known side effects such as liver enzyme abnormalities and hearing impairment is warranted. |
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| Methadone | ↓ methadone | Concentrations of methadone were decreased when coadministered with VIRACEPT. Dosage of methadone may need to be increased when coadministered with VIRACEPT. |
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| Ethinyl estradiol Norethindrone |
↓ ethinyl estradiol ↓ norethindrone |
Concentrations of ethinyl estradiol and norethindrone were decreased when coadministered with VIRACEPT. Alternative or additional contraceptive measures should be used when oral contraceptives containing ethinyl estradiol or norethindrone and VIRACEPT are coadministered. |
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| Sildenafil Vardenafil Tadalafil |
↑ PDE5 Inhibitors | Concomitant use of PDE5 inhibitors and VIRACEPT should be undertaken with caution. May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. • Use of sildenafil (REVATIO) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [ • The following dose adjustments are recommended for use of tadalafil (ADCIRCA™) with VIRACEPT: Start at or adjust ADCIRCA to 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 24 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours, is recommended. Use with increased monitoring for adverse events. |
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| Omeprazole | ↓ nelfinavir | Omeprazole decreases the plasma concentrations of nelfinavir. Concomitant use of proton pump inhibitors and VIRACEPT may lead to a loss of virologic response and development of resistance. |
|
Coadministered |
(mg/day) |
Dose (mg/day) |
Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval) |
AED on MHD Concentration (Mean Change, 90% Confidence Interval) |
| Carbamazepine | 400 to 2000 | 900 | nc1 | 40% decrease [CI: 17% decrease, 57% decrease] |
| Phenobarbital | 100 to 150 | 600 to 1800 | 14% increase [CI: 2% increase, 24% increase] |
25% decrease [CI: 12% decrease, 51% decrease] |
| Phenytoin | 250 to 500 | 600 to 1800 >1200 to 2400 |
nc1,2
up to 40% increase3 [CI: 12% increase, 60% increase] |
30% decrease [CI: 3% decrease, 48% decrease] |
| Valproic acid | 400 to 2800 | 600 to 1800 | nc1 | 18% decrease [CI: 13% decrease, 40% decrease] |
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| DRUG | DESCRIPTION OF INTERACTION | ||
| Sulfonylureas | Hypoglycemia potentiated. | ||
| Methotrexate | Decreases tubular reabsorption; clinical toxicity from methotrexate can result. | ||
| Oral Anticoagulants | Increased bleeding. | ||
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| DRUG | DESCRIPTION OF INTERACTION | ||
| Corticosteroids | Decreases plasma salicylate level; tapering doses of steroids may promote salicylism. | ||
| Acidifying Agents | Increases plasma salicylate levels. | ||
| Alkanizing Agents | Decreased plasma salicylate levels. | ||
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| DRUG | DESCRIPTION OF INTERACTION | ||
| Heparin | Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients. | ||
| Pyrazinamide | Inhibits pyrazinamide-induced hyperuricemia. | ||
| Uricosuric Agents | Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited. | ||
| The following alterations of laboratory tests have been reported during salicylate therapy: | |||
| LABORATORY TESTS | EFFECT OF SALICYLATES | ||
| Thyroid Function | Decreased PBI; increased t3 uptake. | ||
| Urinary Sugar | False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.). | ||
| 5-Hydroxyindole acetic acid | False negative with fluorometric test. | ||
| Acetone ketone bodies | False positive FeCI3 in Gerhardt reaction; red color persists with boiling. | ||
| 17-OH corticosteroids | False reduced values with >4.8g q.d. salicylate. | ||
| Vanilmandelic acid | False reduced values. | ||
| Uric Acid | May increase or decrease depending on dose. | ||
| Prothrombin | Decreased levels; slightly increased prothrombin time. | ||
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Hepatitis C Protease inhibitor (boceprevir) |
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| Interacting Agents | Prescribing Recommendations |
| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone |
Avoid simvastatin |
| Gemfibrozil, cyclosporine, danazol |
Do not exceed 10 mg simvastatin daily |
| Amiodarone, verapamil |
Do not exceed 20 mg simvastatin daily |
| Diltiazem | Do not exceed 40 mg simvastatin daily |
| Grapefruit juice |
Avoid large quantities of grapefruit juice (>1 quart daily) |
| Enzyme | Inhibitors | Inducers |
|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
| Drug Class | Specific Drugs |
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
| 1A2 | 2C9 | 3A4 | 2C19 |
|---|---|---|---|
| Warfarin | Warfarin | Alprazolam | Omeprazole |
| Theophylline | |||
| Propranolol | |||
| Tizanidine |
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| Concomitant Drug Class: Drug Name |
Effect on Concentration of Raltegravir | Clinical Comment |
|---|---|---|
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| atazanavir | ↑ | Atazanavir, a strong inhibitor of UGT1A1, increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended. |
| atazanavir/ritonavir | ↑ | Atazanavir/ritonavir increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended. |
| efavirenz | ↓ | Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed. |
| etravirine | ↓ | Etravirine reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed. |
| tipranavir/ritonavir | ↓ | Tipranavir/ritonavir reduces plasma concentrations of raltegravir. However, since comparable efficacy was observed for this combination relative to other ISENTRESS-containing regimens in Phase 3 studies 018 and 019, no dose adjustment is recommended. |
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| omeprazole | ↑ | Coadministration of medicinal products that increase gastric pH (e.g., omeprazole) may increase raltegravir levels based on increased raltegravir solubility at higher pH. However, since concomitant use of ISENTRESS with proton pump inhibitors and H2 blockers did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended. |
| rifampin | ↓ | Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of raltegravir. The recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin. |
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| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid grapefruit juice |
| |
|
| Tolbutamide; Sulfonylureas | Hypoglycemia potentiated |
| Methotrexate | Decreases tubular reabsorption; clinical toxicity from methotrexate can result |
| Oral Anticoagulants | Increased Bleeding |
| |
|
| Corticosteroids | Decreases plasma salicylate level; tapering doses of steroids may promote salicylism |
| Ammonium Sulfate |
|
| |
|
| Heparin | Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients |
| Pyrazinamide | Inhibits pyrazinamide-induced hyperuricemia |
| Uricosuric Agents | Effect of probenecid, sulfinpyrazone and phenylbutazone inhibited |
| |
|
| Thyroid Function | Decreased PBI; increased T3 uptake |
| Urinary Sugar | False negative with glucose oxidase; false positive with Clinitest with highdose salicylate therapy (2-5 g qd) |
| 5 Hydroxyindole AceticAcid | False negative with fluorometric test |
| Acetone, Ketone Bodies | False positive FeCl3 inGerhardt reaction; red color persists with boiling |
| 17-OH Corticosteroids | False reduced values with >4.8 g qd salicylate |
| Vanilmandelic Acid | False reduced values |
| Uric Acid | May increase or decrease depending on dose |
| Prothrombin | Decreased levels; slightly increased prothrombin time |
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
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Strong CYP34A inhibitors (e.g. itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin |
|
Verapamil, diltiazem |
Do not exceed 10 mg simvastatin daily |
|
Amiodarone, amlodipine, ranolazine |
Do not exceed 20 mg simvastatin daily |
|
Grapefruit juice |
Avoid large quantities of grapefruit juice (>1 quart daily) |
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| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone |
Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine |
Do not exceed 20 mg simvastatin daily |
| Grapefruit juice |
Avoid grapefruit juice |
| AED Coadministered | AED Concentration | Topiramate Concentration |
| Phenytoin | NC or 25% increase |
48% decrease |
| Carbamazepine (CBZ) | NC | 40% decrease |
| CBZ epoxide |
NC | NE |
| Valproic acid | 11% decrease | 14% decrease |
| Phenobarbital | NC | NE |
| Primidone | NC | NE |
| Lamotrigine | NC at TPM doses up to 400 mg/day | 13% decrease |
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400 mg/day for 5 days |
10 mg single dose |
6.9-times LATUDA alone |
9-times LATUDA alone |
Should not be coadministered with LATUDA |
| |
240 mg/ day for 5 days |
20 mg single dose |
2.1- times LATUDA alone |
2.2- times LATUDA alone |
LATUDA dose should not exceed 40 mg/day if coadministered |
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600 mg/day for 8 days |
40 mg single dose |
1/7th of LATUDA alone | 1/5th of LATUDA alone | Should not be coadministered with LATUDA |
| |
600 mg BID for 8 days |
120 mg/day for 8 days |
0.9-times LATUDA alone | 1.1- times LATUDA alone | No LATUDA dose adjustment required. |
| AED Co-administered | AED Concentration | Topiramate Concentration |
|---|---|---|
| NC = Less than 10% change in plasma concentration. NE = Not Evaluated |
||
| Phenytoin | NC or 25% increase |
48% decrease |
| Carbamazepine (CBZ) | NC | 40% decrease |
| CBZ epoxide |
NC | NE |
| Valproic acid | 11% decrease | 14% decrease |
| Phenobarbital | NC | NE |
| Primidone | NC | NE |
| Lamotrigine | NC at TPM doses up to 400 mg/day | 13% decrease |
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| Concomitant Drug Class: Drug Name |
Effect on Concentration of Raltegravir | Clinical Comment |
|---|---|---|
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| atazanavir | ↑ | Atazanavir, a strong inhibitor of UGT1A1, increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended. |
| atazanavir/ritonavir | ↑ | Atazanavir/ritonavir increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended. |
| efavirenz | ↓ | Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed. |
| etravirine | ↓ | Etravirine reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed. |
| tipranavir/ritonavir | ↓ | Tipranavir/ritonavir reduces plasma concentrations of raltegravir. However, since comparable efficacy was observed for this combination relative to other ISENTRESS-containing regimens in Phase 3 studies 018 and 019, no dose adjustment is recommended. |
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||
| boceprevir | ↔ | No dose adjustment required for ISENTRESS or boceprevir. |
| omeprazole | ↑ | Coadministration of medicinal products that increase gastric pH (e.g., omeprazole) may increase raltegravir levels based on increased raltegravir solubility at higher pH. However, since concomitant use of ISENTRESS with proton pump inhibitors and H2 blockers did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended. |
| rifampin | ↓ | Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of raltegravir. The recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin. |
|
|
|
|
|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
|
|
|
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
|
|
|
||
|
|
|||
| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
|
|
|||
|
|
|||
| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone Iodide (including iodine- containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
|
|
|||
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
|
|
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|
|
|
||
|
|
|
||
| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
|
|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
|
|
|||
|
|
|||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
|
|
|||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
|
|
|||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
| DRUG INTERACTIONS |
|
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) | Do not exceed 40 mg atorvastatin daily |
| Enzyme | Inhibitors | Inducers |
|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
| Drug Class | Specific Drugs |
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
|
|
|
|
|
|
||
| Dopamine / Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day). | |
|
|
||
|
|
||
| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | |
|
|
||
| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | |
|
|
||
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | |
|
|
||
|
|
|
|
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | |
|
|
||
|
|
||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | |
|
|
||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | |
|
|
||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms. | |
|
|
|
| Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Amiodarone, verapamil, diltiazem | Do not exceed 10 mg simvastatin daily |
| Amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (> 1 quart daily) |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine | Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide | ↓ lamotrigine | Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels. | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine | Increased lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. | |
|
|
||
| Drug Name | Effect on Concentration of Nevirapine or Concomitant Drug |
Clinical Comment |
|---|---|---|
| Atazanavir/Ritonavir |
↓ Atazanavir ↑ Nevirapine |
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure. |
| Clarithromycin |
↓ Clarithromycin ↑ 14-OH clarithromycin |
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered. |
| Efavirenz |
↓ Efavirenz |
There has been no determination of appropriate doses for the safe and effective use of this combination |
| Ethinyl estradiol and Norethindrone |
↓ Ethinyl estradiol ↓ Norethindrone |
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended. |
| Fluconazole |
↑ Nevirapine |
Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine -associated adverse events. |
| Fosamprenavir |
↓Amprenavir ↑Nevirapine |
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. |
| Fosamprenavir/Ritonavir |
↓Amprenavir ↑Nevirapine |
No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. |
| Indinavir |
↓ Indinavir |
Appropriate doses for this combination are not established, but an increase in the dosage of indinavir may be required. |
| Ketoconazole |
↓ Ketoconazole |
Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. |
| Lopinavir/Ritonavir |
↓Lopinavir |
A dose increase of lopinavir/ritonavir tablets to 500/125 mg twice-daily is recommended when used in combination with nevirapine. A dose increase of lopinavir/ritonavir oral solution to 533/133 mg twice daily with food is recommended in combination with nevirapine. In children 6 months to 12 years of age receiving lopinavir/ritonavir solution, consideration should be given to increasing the dose of lopinavir/ritonavir to 13/3.25 mg/kg for those 7 to <15 kg; 11/2.75 mg/kg for those 15 to 45 kg; and up to a maximum dose of 533/ 133 mg twice daily. Refer to the lopinavir/ritonavir package insert for complete pediatric dosing instructions when lopinavir/ritonavir tablets are used in combination with nevirapine. |
| Methadone |
↓ Methadone |
Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. |
| Nelfinavir |
↓ Nelfinavir M8 Metabolite ↓ Nelfinavir Cmin
|
The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established. |
| Rifabutin |
↑ Rifabutin |
Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. |
| Rifampin |
↓ Nevirapine |
Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead. |
| Saquinavir/Ritonavir |
The interaction between nevirapine and saquinavir/ritonavir has not been evaluated |
The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established. |
|
|
||
|
|
|
|
| Antiarrhythmics |
Amiodarone, disopyramide, lidocaine |
Plasma concentrations may be decreased. |
| Anticonvulsants |
Carbamazepine, clonazepam, ethosuximide |
Plasma concentrations may be decreased. |
| Antifungals |
Itraconazole |
Plasma concentrations of some azole antifungals may be decreased. Nevirapine and itraconazole should not be administered concomitantly due to a potentialdecrease in itraconazole plasma concentrations. |
| Calcium channel blockers |
Diltiazem, nifedipine, verapamil |
Plasma concentrations may be decreased. |
| Cancer chemotherapy |
Cyclophosphamide |
Plasma concentrations may be decreased. |
| Ergot alkaloids |
Ergotamine |
Plasma concentrations may be decreased. |
| Immunosuppressants |
Cyclosporin, tacrolimus, sirolimus |
Plasma concentrations may be decreased. |
| Motility agents |
Cisapride |
Plasma concentrations may be decreased. |
| Opiate agonists |
Fentanyl |
Plasma concentrations may be decreased. |
| Antithrombotics |
Warfarin |
Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended. |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | |
Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide | |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels. | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | |
Increased lamotrigine concentrations slightly more than 2 fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
|
|
|
|
|
|
| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
|
|
|
|
|
|
| Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
|
|
|
| Amiodarone Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
|
|
|
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
|
|
|
|
|
|
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
| Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
|
|
|
|
|
|
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
|
|
|
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
|
|
|
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
| Alpha-Blocker | Simultaneous dosing of Vardenafil 5 mg and Alpha-Blocker, Placebo-Subtracted |
Dosing of Vardenafil 5 mg and Alpha-Blocker Separated by 6 Hours, Placebo-Subtracted |
|
| Terazosin 5 or 10 mg daily |
Standing SBP | -3 (-6.7, 0.1) | -4 (-7.4, -0.5) |
| Supine SBP | -4 (-6.7, -0.5) | -4 (-7.1, -0.7) | |
| Tamsulosin 0.4 mg daily |
Standing SBP Supine SBP |
-6 (-9.9, -2.1) -4 (-7.0, -0.8) |
-4 (-8.3, -0.5) -5 (-7.9, -1.7) |
| Vardenafil 10 mg Placebo-subtracted |
Vardenafil 20 mg Placebo-subtracted |
|
| Standing SBP | -4 (-6.8, -0.3) | -4 (-6.8, -1.4) |
| Supine SBP | -5 (-8.2, -0.8) | -4 (-6.3, -1.8) |
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitors (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
|
|
|
|
e.g., |
|
|
e.g., tri-iodothyronine |
2 weeks |
|
|
2 weeks |
|
|
|
|
|
|
|
corticosteroids, sulfonamides tolbutamide, perchlorate phenylbutazone lithium |
1 week 1 week 1-2 weeks 4 weeks |
| DRUG | DESCRIPTION OF INTERACTION |
| Sulfonylureas | Hypoglycemia potentiated. |
| Methotrexate |
|
|
|
Increased bleeding. |
| DRUG | DESCRIPTION OF INTERACTION |
| Corticosteroids | Decreases plasma salicylate level; tapering doses of steroids may promote salicylism. |
| Acidifying Agents | Increases plasma salicylate level. |
| Alkanizing Agents | Decreased plasma salicylate levels. |
| DRUG | DESCRIPTION OF INTERACTION |
|
|
|
| Pyrazinamide | Inhibits pyrazinamide induced hyperuricemia. |
| Uricosuric Agents | Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited. |
| LABORATORY TESTS | EFFECT OF SALICYLATES |
| Thyroid Function | Decreased PBI; increased T3 uptake. |
| Urinary Sugar | False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.). |
| 5-Hydroxyindole acetic acid | False negative with fluorometric test. |
| Acetone, ketone bodies | False positive FeCl3 in Gerhardt reaction; red color persists with boiling. |
| 17-OH corticosteroids | False reduced values with >4.8g q.d. salicylate. |
| Vanilmandelic acid | False reduced values. |
| Uric acid | May increase or decrease depending on dose. |
| Prothrombin | Decreased levels; slightly increased prothrombin time. |
| albuterol, | famotidine | nizatidine |
| systemic and inhaled | felodipine | norfloxacin |
| amoxicillin | finasteride | ofloxacin |
| ampicillin, | hydrocortisone | omeprazole |
| with or without | isoflurane | prednisone, prednisolone |
| sulbactam | isoniazid | ranitidine |
| atenolol | isradipine | rifabutin |
| azithromycin | influenza vaccine | roxithromycin |
| caffeine, | ketoconazole | sorbitol |
| dietary ingestion | lomefloxacin | (purgative doses do not |
| cefaclor | mebendazole | inhibit theophylline |
| co-trimoxazole | medroxyprogesterone | absorption) |
| (trimethoprim and | methylprednisolone | sucralfate |
| sulfamethoxazole) | metronidazole | terbutaline, systemic |
| diltiazem | metoprolol | terfenadine |
| dirithromycin | nadolol | tetracycline |
| enflurane | nifedipine | tocainide |
| Drug Class: Drug Name | Clinical Comment |
|---|---|
| Alpha 1-adrenoreceptor antagonist: alfuzosin |
Potentially increased alfuzosin concentrations can result in hypotension. |
| Antiarrhythmics: amiodarone, quinidine |
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as cardiac arrhythmias. |
| Antimycobacterial: rifampin |
May lead to loss of virologic response and possible resistance to VIRACEPT or other coadministered antiretroviral agents. |
| Ergot Derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine |
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. |
| Herbal Products: St. John's wort (hypericum perforatum) |
May lead to loss of virologic response and possible resistance to VIRACEPT or other coadministered antiretroviral agents. |
| HMG-CoA Reductase Inhibitors: lovastatin, simvastatin |
Potential for serious reactions such as risk of myopathy including rhabdomyolysis. |
| Neuroleptic: pimozide |
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as cardiac arrhythmias. |
| PDE5 inhibitor: sildenafil (REVATIO) [for treatment of pulmonary arterial hypertension] |
A safe and effective dose has not been established when used with VIRACEPT. There is increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, prolonged erection, and syncope). |
| Proton Pump Inhibitors | Omeprazole decreases the plasma concentrations of nelfinavir. Concomitant use of proton pump inhibitors and VIRACEPT may lead to a loss of virologic response and development of resistance. |
| Sedative/Hypnotics: midazolam, triazolam |
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as prolonged or increased sedation or respiratory depression. |
| Concomitant Drug Class: Drug Name | Effect on Concentration | Clinical Comment | |
|---|---|---|---|
| HIV-Antiviral Agents | |||
| Non-nucleoside Reverse Transcriptase Inhibitors: | Appropriate doses for these combinations, with respect to safety and efficacy, have not been established. | ||
| delavirdine | ↑ nelfinavir ↓ delavirdine |
||
| nevirapine | ↓ nelfinavir (Cmin) | ||
| Nucleoside Reverse Transcriptase Inhibitor: didanosine |
It is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after VIRACEPT (given with food). |
||
| Protease Inhibitors: | Appropriate doses for these combinations, with respect to safety and efficacy, have not been established. | ||
| indinavir | ↑ nelfinavir ↑ indinavir |
||
| ritonavir | ↑ nelfinavir | ||
| saquinavir | ↑ saquinavir | ||
| Other Agents | |||
| Anti-coagulant: warfarin |
warfarin | Coadministration of warfarin and VIRACEPT may affect concentrations of warfarin. It is recommended that the INR (international normalized ratio) be monitored carefully during treatment with VIRACEPT, especially when commencing therapy. | |
| Anti-convulsants: | May decrease nelfinavir plasma concentrations. VIRACEPT may not be effective due to decreased nelfinavir plasma concentrations in patients taking these agents concomitantly. | ||
| carbamazepine phenobarbital |
↓ nelfinavir | ||
| Anti-convulsant: | Phenytoin plasma/serum concentrations should be monitored; phenytoin dose may require adjustment to compensate for altered phenytoin concentration. | ||
| phenytoin | ↓ phenytoin | ||
| Anti-depressant: trazodone | ↑ trazodone | Concomitant use of trazodone and VIRACEPT may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as VIRACEPT, the combination should be used with caution and a lower dose of trazodone should be considered. | |
| Anti-gout colchicine |
↑ colchicine | Treatment of gout flares– coadministration of colchicine in patients on VIRACEPT: coadministration of colchicine in patients on VIRACEPT: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. coadministration of colchicine in patients on VIRACEPT: Patients with renal or hepatic impairment should not be given colchicine with VIRACEPT. |
|
| Anti-Mycobacterial: | It is recommended that the dose of rifabutin be reduced to one-half the usual dose when administered with VIRACEPT; 1250 mg BID is the preferred dose of VIRACEPT when coadministered with rifabutin. | ||
| rifabutin | ↑ rifabutin ↓ nelfinavir (750 mg TID) ↔ nelfinavir (1250 mg BID) |
||
| Endothelin receptor antagonists: bosentan |
↑ bosentan |
|
|
| HMG-CoA Reductase Inhibitor: | Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with VIRACEPT. | ||
| atorvastatin | ↑ atorvastatin | ||
| rosuvastatin | ↑ rosuvastatin | ||
| Immuno-suppressants: | Plasma concentrations may be increased by VIRACEPT. | ||
| cyclosporine tacrolimus sirolimus |
↑ immuno-suppressants | ||
| Inhaled beta agonist: salmeterol |
↑ salmeterol | Concurrent administration of salmeterol with VIRACEPT is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. | |
| Inhaled/nasal steroid: Fluticasone | ↑ fluticasone | Concomitant use of fluticasone propionate and VIRACEPT may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use. | |
| Macrolide Antibiotic: azithromycin |
↑ azithromycin |
Dose adjustment of azithromycin is not recommended, but close monitoring for known side effects such as liver enzyme abnormalities and hearing impairment is warranted. | |
| Narcotic Analgesic: | Dosage of methadone may need to be increased when coadministered with VIRACEPT. | ||
| methadone | ↓ methadone | ||
| Oral Contraceptive: | Alternative or additional contraceptive measures should be used when oral contraceptives and VIRACEPT are coadministered. | ||
| ethinyl estradiol | ↓ ethinyl estradiol | ||
| PDE5 Inhibitors: sildenafil vardenafil tadalafil |
↑ PDE5 Inhibitors |
Concomitant use of PDE5 inhibitors and VIRACEPT should be undertaken with caution.
|
|
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
|
Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19% | |
| Carbamazepine (CBZ) and CBZ epoxide |
|
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate |
|
Increased lamotrigine concentrations slightly more than 2 fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
|
|---|---|
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) | Do not exceed 40 mg atorvastatin daily |
| Interacting Drug | Interaction |
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1) |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2) |
| Antidiabetic agents | Carefully monitor blood glucose (5.11, 7.3) |
|
|
|
|
|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
|
|
|
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
|
|
|
|
|
|
| Carbamazepine | 400-2000 | 900 | nc |
|
| Phenobarbital | 100-150 | 600-1800 |
|
|
| Phenytoin | 250-500 |
|
|
|
| Valproic acid | 400-2800 | 600-1800 | nc |
|
| albuterol, | famotidine | nizatidine |
| systemic and inhaled | felodipine | norfloxacin |
| amoxicillin | finasteride | ofloxacin |
| ampicillin, | hydrocortisone | omeprazole |
| with or without | isoflurane | prednisone, prednisolone |
| sulbactam | isoniazid | ranitidine |
| atenolol | isradipine | rifabutin |
| azithromycin | influenza vaccine | roxithromycin |
| caffeine, | ketoconazole | sorbitol |
| dietary ingestion | lomefloxacin | (purgative doses do not |
| cefaclor | mebendazole | inhibit theophylline |
| co-trimoxazole | medroxyprogesterone | absorption) |
| (trimethoprim and | methylprednisolone | sucralfate |
| sulfamethoxazole) | metronidazole | terbutaline, systemic |
| diltiazem | metoprolol | terfenadine |
| dirithromycin | nadolol | tetracycline |
| enflurane | nifedipine | tocainide |
| Coadministered Drug |
Dosing Schedule |
|
Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
|
Risperidone Dose Recommendation |
|
|
Coadministered Drug |
Risperidone |
AUC |
Cm
a
x
|
|
| Enzyme (CYP2D6) Inhibitors |
|
|
|
|
|
| Fluoxetine |
20 mg/day |
2 or 3 mg twice daily |
1.4 |
1.5 |
Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine |
10 mg/day |
4 mg/day |
1.3 |
- |
Re-evaluate dosing. |
|
|
20 mg/day |
4 mg/day |
1.6 |
- |
Do not exceed 8 mg/day |
|
|
40 mg/day |
4 mg/day |
1.8 |
- |
|
| Enzyme (CYP3A/ PgP inducers) |
|
|
|
|
|
| Carbamazepine |
573 ± 168 mg/day |
3 mg twice daily |
0.51 |
0.55 |
Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors |
|
|
|
|
|
| Ranitidine |
150 mg twice daily |
1 mg single dose |
1.2 |
1.4 |
Dose adjustment not needed |
| Cimetidine |
400 mg twice daily |
1 mg single dose |
1.1 |
1.3 |
Dose adjustment not needed |
| Erythromycin |
500 mg four times daily |
1 mg single dose |
1.1 |
0.94 |
Dose adjustment not needed |
| Other Drugs |
|
|
|
|
|
| Amitriptyline |
50 mg twice daily |
3 mg twice daily |
1.2 |
1.1 |
Dose adjustment not needed |
|
|
| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
| Concomitant Drug |
Effect on Concentration of Lamotrigine or Concomitant Drug |
Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine ↓ levonorgestrel |
Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%. |
| Carbamazepine (CBZ) and CBZ epoxide |
↓ lamotrigine ? CBZ epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase CBZ epoxide levels |
| Phenobarbital/Primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40%. |
| Valproate |
↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
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|
Multivalent cation-containing products including antacids, metal cation or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. |
|
Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding |
|
Antidiabetic agent |
Carefully monitor blood glucose ( |
| AED Co-administered | AED Concentration | Topiramate Concentration |
|---|---|---|
| NC = Less than 10% change in plasma concentration. NE = Not Evaluated |
||
| Phenytoin | NC or 25% increase |
48% decrease |
| Carbamazepine (CBZ) | NC | 40% decrease |
| CBZ epoxide |
NC | NE |
| Valproic acid | 11% decrease | 14% decrease |
| Phenobarbital | NC | NE |
| Primidone | NC | NE |
| Lamotrigine | NC at TPM doses up to 400 mg/day | 13% decrease |
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Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
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Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
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|
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
|
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|
|
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
|
|
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
|
|
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
|
|
Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
|
|
Thereapy wih interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
|
|
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
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Coadministered |
(mg/day) |
Dose (mg/day) |
Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval) |
AED on MHD Concentration (Mean Change, 90% Confidence Interval) |
| Carbamazepine | 400 to 2000 | 900 | nc1 | 40% decrease [CI: 17% decrease, 57% decrease] |
| Phenobarbital | 100 to 150 | 600 to 1800 | 14% increase [CI: 2% increase, 24% increase] |
25% decrease [CI: 12% decrease, 51% decrease] |
| Phenytoin | 250 to 500 | 600 to 1800 >1200 to 2400 |
nc1,2
up to 40% increase3 [CI: 12% increase, 60% increase] |
30% decrease [CI: 3% decrease, 48% decrease] |
| Valproic acid | 400 to 2800 | 600 to 1800 | nc1 | 18% decrease [CI: 13% decrease, 40% decrease] |
|
|
|
||
|
|
|||
| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
|
|
|||
|
|
|||
| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
|
|
|||
|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
| |
|||
|
|
|
||
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
||
|
|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
| |
|||
| |
|||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
|
|
|||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
|
|
|||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
|
|
|
||
|
|
|||
| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
|
|
|||
|
|
|||
| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone Iodide (including iodine- containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
|
|
|||
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
|
|
|||
|
|
|
||
|
|
|
||
| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
|
|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
|
|
|||
|
|
|||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
|
|
|||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
|
|
|||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
|
|
|
|
|
| ciprofloxacin | melphalan | azapropazon | cimetidine |
| gentamicin | colchicine | ranitidine | |
| tobramycin |
|
diclofenac | |
| vancomycin | amphotericin B | naproxen |
|
| trimethoprim with sulfamethoxazole | ketoconazole | sulindac | tacrolimus |
|
|
|||
| fibric acid derivatives | |||
| (e.g.,bezafibrate, fenofibrate) methotrexate |
|
|
|
|
|
|
| diltiazem | fluconazole | azithromycin | methylprednisolone | allopurinol |
| nicardipine | itraconazole | clarithromycin | amiodarone | |
| verapamil | ketoconazole | erythromycin | bromocriptine | |
| voriconazole | quinupristin/ | colchicine | ||
| dalfopristin | danazol | |||
| imatinib | ||||
| metoclopramide | ||||
| nefazodone | ||||
| oral contraceptives |
|
|
|
|
| nafcillin | carbamazepine | bosentan |
| rifampin | oxcarbazepine | octreotide |
| phenobarbital | orlistat | |
| phenytoin | sulfinpyrazone | |
| St. John's Wort | ||
| terbinafine | ||
| ticlopidine |
| Concomitant Drug Class or Food | Noted or anticipated Outcome | Clinical Comment |
|---|---|---|
|
atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin |
Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality) | Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy. |
|
fibrates, gemfibrozil |
||
|
digoxin |
P-gp substrate; rhabdomyolysis has been reported |
| Enzyme | Inhibitors | Inducers |
|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
| Drug Class | Specific Drugs |
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
|
|
|
|
|
|
|
Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
|
|
|
|
|
|
|
Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
|
|
|
|
Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
|
|
|
|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function. |
|
|
|
|
|
|
|
Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
|
Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4 . Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
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Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
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Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
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- Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
|
- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
|
- Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
|
- Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
|
- Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
|
- (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
|
Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
|
|---|---|
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) | Do not exceed 40 mg atorvastatin daily |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
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| Amiodarone Iodide (including iodine- containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
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|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
|
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|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
|
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| CYP2C9 |
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast |
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 |
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton |
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 |
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton |
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
|
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|
| Anticoagulants |
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents |
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents |
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors |
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
| Drug Class: Drug Name | Clinical Comment |
|
|
May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of NNRTIs. |
|
|
CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. |
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|
May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of NNRTIs or other coadministered antiviral agents. |
|
|
CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. |
|
|
CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. |
|
( |
May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of NNRTIs. |
|
|
Potential for serious reactions such as risk of myopathy including rhabdomyolysis. |
|
|
CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. |
|
|
CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression. |
|
|
Effect on Concentration of Delavirdine or Concomitant Drug | Clinical Comment |
| HIV-Antiviral Agents | ||
| Amprenavir | ↑Amprenavir | Appropriate doses of this combination with respect to safety, efficacy, and pharmacokinetics have not been established. |
| Didanosinea |
|
Administration of didanosine (buffered tablets) and RESCRIPTOR should be separated by at least 1 hour. |
| Indinavira | ↑Indinavir | A dose reduction of indinavir to 600 mg 3 times daily should be considered when RESCRIPTOR and indinavir are coadministered. |
| Lopinavir/Ritonavir |
|
Appropriate doses of this combination with respect to safety, efficacy, and pharmacokinetics have not been established. |
| Nelfinavira |
|
Appropriate doses of this combination with respect to safety, efficacy, and pharmacokinetics have not been established. (See CLINICAL PHARMACOLOGY: Tables 1 and 2.) |
| Ritonavir | ↑Ritonavir | Appropriate doses of this combination with respect to safety, efficacy, and pharmacokinetics have not been established. |
|
|
|
A dose reduction of saquinavir (soft gelatin capsules) may be considered when RESCRIPTOR and saquinavir are coadministered (see CLINICAL PHARMACOLOGY: Table 1). Appropriate doses with respect to safety, efficacy, and pharmacokinetics have not been established. |
| Other Agents | ||
|
|
↓Delavirdine | Doses of an antacid and RESCRIPTOR should be separated by at least 1 hour, because the absorption of delavirdine is reduced when coadministered with antacids. |
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|
↓Delavirdine | These agents increase gastric pH and may reduce the absorption of delavirdine. Although the effect of these drugs on delavirdine absorption has not been evaluated, chronic use of these drugs with RESCRIPTOR is not recommended. |
|
|
↓Delavirdine | These agents increase gastric pH and may reduce the absorption of delavirdine. Although the effect of these drugs on delavirdine absorption has not been evaluated, chronic use of these drugs with RESCRIPTOR is not recommended. |
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↑Amphetamines |
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|
↑Trazodone | Concomitant use of trazodone and RESCRIPTOR may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as RESCRIPTOR, the combination should be used with caution and a lower dose of trazadone should be considered. |
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|
↑Antiarrhythmics | Use with caution. Increased bepridil exposure may be associated with life-threatening reactions such as cardiac arrhythmias. |
| Amiodarone,lidocaine (systemic), quinidine, flecainide, propafenone | Caution is warranted and therapeutic concentration monitoring is recommended, if available, for antiarrhythmics when coadministered with RESCRIPTOR. | |
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↑Warfarin | It is recommended that INR (international normalized ratio) be monitored. |
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↑Calcium channel blockers | Caution is warranted and clinical monitoring of patients is recommended. |
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↓Delavirdine | Use with caution. RESCRIPTOR may be less effective due to decreased delavirdine plasma concentrations in patients taking these agents concomitantly. |
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↑Sildenafil | Sildenafil should not exceed a maximum single dose of 25 mg in a 48-hour period. |
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|
Use lowest possible dose of atorvastatin or cerivastatin, or fluvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin in combination with RESCRIPTOR. |
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↑Immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with RESCRIPTOR. |
|
|
↑Fluticasone | Concomitant use of fluticasone propionate and RESCRIPTOR may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use. |
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|
↑Methadone | Dosage of methadone may need to be decreased when coadministered with RESCRIPTOR. |
|
|
↑Ethinyl estradiol | Concentrations of ethinyl estradiol may increase. However, the clinical significance is unknown. |
| albuterol, | diltiazem | medroxyprogesterone | roxithromycin |
| systemic and inhaled | dirithromycin | methylprednisolone | sorbitol |
| amoxicillin | enflurane | metronidazole | (purgative doses |
| ampicillin, | famotidine | metoprolol | do not inhibit |
| with or without | felodipine | nadolol | theophylline |
| sulbactam | finasteride | nifedipine | absorption) |
| atenolol | hydrocortisone | nizatidine | sucralfate |
| azithromycin | isoflurane | norfloxacin | terbutaline, systemic |
| caffeine, | isoniazid | ofloxacin | terfenadine |
| dietary ingestion | isradipine | omeprazole | tetracycline |
| cefaclor | influenza vaccine | prednisone, | tocainide |
| co-trimoxazole | ketoconazole | prednisolone | |
| (trimethoprim and | lomefloxacin | ranitidine | |
| sulfamethoxazole) | mebendazole | rifabutin | |
| I. Due to the competition of salicylate with other drugs for binding to serum albumin the following drug interactions may occur: |
||
| Drug | Description of Interaction | |
|---|---|---|
| Tolbutamide; Sulfonylureas | Hypoglycemia potentiated | |
| Methotrexate | Decrease tubular reabsorption; clinical toxicity from methotrexate can result | |
| Oral Anticoagulants | Increased bleeding | |
|
II. Drugs changing salicylate levels by altering renal tubular reabsorption: |
||
| Drug | Description of Interaction | |
| Corticosteroids | Decreases plasma salicylate level; tapering doses of steroids may promote salicylism | |
| Ammonium Sulfate | Increases plasma salicylate level | |
|
III. Drugs with complicated interactions with salicylates: |
||
| Drug | Description of Interaction | |
| Heparin | Salicylate decreases platelet adhesivesness and interferes with hemostasis in heparin-treated patients | |
| Pyrazinamide | Inhibits pyrazinamide-induced hyperuricemia | |
| Uricosuric Agents | Effect of probenecid, sulfinpyrazone and phenylbutazone inhibited | |
|
The following alterations of laboratory tests have been reported during salicylate therapy6: |
||
| Laboratory Tests | Effect of Salicylates | |
| Thyroid Function | Decreased PBI; increased T3 uptake | |
| Urinary Sugar | False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2 - 5 g qd) | |
| 5 Hydroxyindole Acetic Acid | False negative with fluorometric test | |
| Acetone, Ketone Bodies | False positive FeCl3 in Gerhardt reaction; red color persists with boiling | |
| 17-OH Corticosteroids | False reduced values with >4.8 g qd salicylate | |
| Vanilmandelic Acid | False reduced values | |
| Uric Acid | May increase or decrease depending on dose | |
| Prothrombin | Decreased levels; slightly increased prothrombin time | |
| Co-administered Drug | Dosing Schedule | Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (Ratio |
Risperidone Dose Recommendation | ||
| Co-administered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6) Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
| Interacting Agents | Prescribing Recommendations |
| Strong CYP3A4 inhibitors (e.g.,Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin |
| Verapamil, diltiazem |
Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine |
Do not exceed 20 mg simvastatin daily |
| Grapefruit juice |
Avoid large quantities of grapefruit juice (>1 quart daily) |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
||
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|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
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| |
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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|||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
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|||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
| Interacting Agents | Prescribing Recommendations |
|---|---|
| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone |
Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine |
Do not exceed 20 mg simvastatin daily |
| Grapefruit juice |
Avoid grapefruit juice |
|
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|
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg. ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine ↓levonorgestrel | Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%. |
| Carbamazepine (CBZ) and CBZ epoxide | ↓ lamotrigine ? CBZ epoxide | Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase CBZ epoxide levels |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine ? valproate | Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
| Drug Class: Drug Name |
|
|---|---|
| Antiarrhythmics: amiodarone, quinidine |
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as cardiac arrhythmias. |
| Antimycobacterial: rifampin |
May lead to loss of virologic response and possible resistance to VIRACEPT or other coadministered antiretroviral agents. |
| Ergot Derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine |
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. |
| Herbal Products: St. John's wort (hypericum perforatum) |
May lead to loss of virologic response and possible resistance to VIRACEPT or other coadministered antiretroviral agents. |
| HMG-CoA Reductase Inhibitors: lovastatin, simvastatin |
Potential for serious reactions such as risk of myopathy including rhabdomyolysis. |
| Neuroleptic: pimozide |
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as cardiac arrhythmias. |
| Proton Pump Inhibitors | Omeprazole decreases the plasma concentrations of nelfinavir. Concomitant use of proton pump inhibitors and VIRACEPT may lead to a loss of virologic response and development of resistance. |
| Sedative/Hypnotics: midazolam, triazolam |
CONTRAINDICATED due to potential for serious and/or life threatening reactions such as prolonged or increased sedation or respiratory depression. |
| Concomitant Drug Class: Drug Name | Effect on Concentration | Clinical Comment | |
|---|---|---|---|
| HIV-Antiviral Agents | |||
| Protease Inhibitors: | Appropriate doses for these combinations, with respect to safety and efficacy, have not been established. | ||
| indinavir | ↑ nelfinavir ↑ indinavir |
||
| ritonavir | ↑ nelfinavir | ||
| saquinavir | ↑ saquinavir | ||
| Non-nucleoside Reverse Transcriptase Inhibitors: | Appropriate doses for these combinations, with respect to safety and efficacy, have not been established. | ||
| delavirdine | ↑ nelfinavir ↓ delavirdine |
||
| nevirapine | ↓ nelfinavir (Cmin) | ||
| Nucleoside Reverse Transcriptase Inhibitor: didanosine |
It is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after VIRACEPT (given with food). |
||
| Other Agents | |||
| Anti-Convulsants: | May decrease nelfinavir plasma concentrations. VIRACEPT may not be effective due to decreased nelfinavir plasma concentrations in patients taking these agents concomitantly. | ||
| carbamazepine phenobarbital |
↓ nelfinavir | ||
| Anti-Convulsant: | Phenytoin plasma/serum concentrations should be monitored; phenytoin dose may require adjustment to compensate for altered phenytoin concentration. | ||
| phenytoin | ↓ phenytoin | ||
| Anti-Mycobacterial: | It is recommended that the dose of rifabutin be reduced to one-half the usual dose when administered with VIRACEPT; 1250 mg BID is the preferred dose of VIRACEPT when coadministered with rifabutin. | ||
| rifabutin | ↑ rifabutin ↓ nelfinavir (750 mg TID) ↔ nelfinavir (1250 mg BID) |
||
| PDE5 Inhibitors: sildenafil vardenafil tadalafil |
↑ PDE5 Inhibitors | Concomitant use of PDE5 inhibitors and VIRACEPT should be undertaken with caution. If concomitant use of PDE5 inhibitors and VIRACEPT is required, sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours, is recommended. | |
| HMG-CoA Reductase Inhibitor: | Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with VIRACEPT. | ||
| atorvastatin | ↑ atorvastatin | ||
| rosuvastatin | ↑ rosuvastatin | ||
| Immuno-suppressants: | Plasma concentrations may be increased by VIRACEPT. | ||
| cyclosporine tacrolimus sirolimus |
↑ immuno-suppressants | ||
| Narcotic Analgesic: | Dosage of methadone may need to be increased when coadministered with VIRACEPT. | ||
| methadone | ↓ methadone | ||
| Oral Contraceptive: | Alternative or additional contraceptive measures should be used when oral contraceptives and VIRACEPT are coadministered. | ||
| ethinyl estradiol | ↓ ethinyl estradiol | ||
| Macrolide Antibiotic: azithromycin |
↑ azithromycin |
Dose adjustment of azithromycin is not recommended, but close monitoring for known side effects such as liver enzyme abnormalities and hearing impairment is warranted. | |
| Inhaled/nasal steroid: Fluticasone | ↑ fluticasone | Concomitant use of fluticasone propionate and VIRACEPT may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use. | |
| Antidepressant: trazodone | ↑ trazodone | Concomitant use of trazodone and VIRACEPT may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as VIRACEPT, the combination should be used with caution and a lower dose of trazodone should be considered. | |
| |
|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding |
| Antidiabetic agents | Carefully monitor blood glucose ( |
| DRUG | EFFECT |
|---|---|
| Monoamine Oxidase (MAO) Inhibitors |
Hypertension |
| Enzyme | Inhibitors | Inducers |
|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
| Drug Class | Specific Drugs |
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
| Interacting Agents | Prescribing Recommendations |
|---|---|
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
|
|
|
(mg/day) |
Concentration (Mean Change, 90% Confidence Interval) |
AED on MHD Concentration (Mean Change, 90% Confidence Interval) |
| Carbamazepine | 400 to 2000 | 900 | nc1 | 40% decrease [CI: 17% decrease, 57% decrease] |
| Phenobarbital | 100 to 150 | 600 to 1800 | 14% increase [CI: 2% increase, 24% increase] |
25% decrease [CI: 12% decrease, 51% decrease] |
| Phenytoin | 250 to 500 | 600 to 1800 >1200 to 2400 |
nc1,2
up to 40% increase3 [CI: 12% increase, 60% increase] |
30% decrease [CI: 3% decrease, 48% decrease] |
| Valproic acid | 400 to 2800 | 600 to 1800 | nc1 | 18% decrease [CI: 13% decrease, 40% decrease] |
|
|
|
| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid grapefruit juice |
| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of this product. |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding |
| Antidiabetic agents |
Carefully monitor blood glucose |
|
|
|
| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine, danazol | Do not exceed 10 mg simvastatin daily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
|
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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|||
| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
|
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|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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||
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
||
|
|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
| |
|||
| |
|||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
|
|
|||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
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|
|||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
| AED co-administered | AED Concentration | Topiramate Concentration |
| Phenytoin | NC or 25% increase |
48% decrease |
| Carbamazaepine (CBZ) | NC | 40% decrease |
| CBZ epoxide |
NC | NE |
| Valproic acid | 11% decrease | 14% decrease |
| Phenobarbital | NC | NE |
| Primidone | NC | NE |
| Lamotrigine | NC at TPM doses up to 400mg/day | 13% decrease |
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If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once a day. |
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| Concomitant Drug Class or Food | Noted or anticipated Outcome | Clinical Comment |
|---|---|---|
|
atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin |
Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality) | Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy. |
|
fibrates, gemfibrozil |
||
|
digoxin |
P-gp substrate; rhabdomyolysis has been reported |
|
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|
| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine, danazol | Do not exceed 10 mg simvastatin daily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Diltiazem | Do not exceed 40 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
| Coadministered Drug | Dosing Schedule | Effect on Active Moiety(Risperidone + 9- Hydroxy-Risperidone (Ratio*) | Risperidone Dose Recommendation | ||
| *Change relative to reference | |||||
| Coadministered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6) Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 mg twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/ PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
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Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
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Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
|
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|
Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
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|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function. |
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Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
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|
|
Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4 . Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
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Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
|
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|
|
Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
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|
- Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
|
- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
|
- Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
|
- Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
|
- Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
|
- (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
|
Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
| blood dyscrasias - see cancer collagen vascular disease congestive heart failure |
diarrhea elevated temperature hepatic disorders infectious hepatitis jaundice |
hyperthyroidism poor nutritional state steatorrhea vitamin K deficiency |
| Classes of Drugs | |||
| 5-lipoxygenase Inhibitor Adrenergic Stimulants, Central Alcohol Abuse Reduction Preparations Analgesics Anesthetics, Inhalation Antiandrogen Antiarrhythmics† Antibiotics† Aminoglycosides (oral) Cephalosporins, parenteral Macrolides Miscellaneous Penicillins, intravenous, high dose Quinolones (fluoroquinolones) Sulfonamides, long acting Tetracyclines Anticoagulants Anticonvulsants† Antidepressants† Antimalarial Agents Antineoplastics† Antiparasitic/Antimicrobials |
Antiplatelet Drugs/Effects Antithyroid Drugs† Beta-Adrenergic Blockers Cholelitholytic Agents Diabetes Agents, Oral Diuretics† Fungal Medications, Intravaginal, Systemic† Gastric Acidity and Peptic Ulcer Agents† Gastrointestinal Prokinetic Agents Ulcerative Colitis Agents Gout Treatment Agents Hemorrheologic Agents Hepatotoxic Drugs Hyperglycemic Agents Hypertensive Emergency Agents Hypnotics† Hypolipidemics† Bile Acid-Binding Resins† Fibric Acid Derivatives HMG-CoA Reductase Inhibitors† |
Leukotriene Receptor Antagonist Monoamine Oxidase Inhibitors Narcotics, prolonged Nonsteroidal Anti- Inflammatory Agents Proton Pump Inhibitors Psychostimulants Pyrazolones Salicylates Selective Serotonin Reuptake Inhibitors Steroids, Adrenocortical† Steroids, Anabolic (17-Alkyl Testosterone Derivatives) Thrombolytics Thyroid Drugs Tuberculosis Agents† Uricosuric Agents Vaccines Vitamins† |
|
| Specific Drugs Reported | |||
| also: other medications affecting blood elements which may modify hemostasis dietary deficiencies prolonged hot weather unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported. |
|||
| acetaminophen alcohol† allopurinol aminosalicylic acid amiodarone HCl argatroban aspirin atenolol atorvastatin† azithromycin bivalirudin capecitabine cefamandole cefazolin cefoperazone cefotetan cefoxitin ceftriaxone celecoxib cerivastatin chenodiol chloramphenicol chloral hydrate† chlorpropamide cholestyramine† cimetidine ciprofloxacin cisapride clarithromycin clofibrate cyclophosphamide† danazol dextran dextrothyroxine diazoxide |
diclofenac dicumarol diflunisal disulfiram doxycycline erythromycin esomeprazole ethacrynic acid ezetimibe fenofibrate fenoprofen fluconazole fluorouracil fluoxetine flutamide fluvastatin fluvoxamine gefitinib gemifibrozil glucagon halothane heparin ibuprofen ifosfamide indomethacin influenza virus vaccine itraconazole ketoprofen ketorolac lansoprazole lepirudin levamisole levofloxacin levothyroxine liothyronine |
lovastatin mefenamic acid methimazole† methyldopa methylphenidate methylsalicylate ointment (topical) metronidazole miconazole (intravaginal, oral, systemic) moricizine hydrochloride† nalidixic acid naproxen neomycin norfloxacin ofloxacin olsalazine omeprazole oxandrolone oxaprozin oxymetholone pantoprazole paroxetine penicillin G, intravenous pentoxifylline phenylbutazone phenytoin† piperacillin piroxicam pravastatin† prednisone† propafenone |
propoxyphene propranolol propylthiouracil† quinidine quinine rabeprazole ranitidine† rofecoxib sertraline simvastatin stanozolol streptokinase sulfamethizole sulfamethoxazole sulfinpyrazone sulfisoxazole sulindac tamoxifen tetracycline thyroid ticarcillin ticlopidine tissue plasminogen activator (t-PA) tolbutamide tramadol trimethoprim/ sulfamethoxazole urokinase valdecoxib valproate vitamin E warfarin overdose zafirlukast zileuton |
| edema hereditary coumarin resistance hyperlipemia |
hypothyroidism nephrotic syndrome |
| Classes of Drugs | ||
| Adrenal Cortical Steroid Inhibitors Antacids Antianxiety Agents Antiarrhythmics† Antibiotics† Anticonvulsants† Antidepressants† Antihistamines Antineoplastics† |
Antipsychotic Medications Antithyroid Drugs† Barbiturates Diuretics† Enteral Nutritional Supplements Fungal Medications, Systemic† Gastric Acidity and Peptic Ulcer Agents† Hypnotics† |
Hypolipidemics† Bile Acid-Binding Resins† HMG-CoA Reductase Inhibitors† Immunosuppressives Oral Contraceptives, Estrogen Containing Selective Estrogen Receptor Modulators Steroids, Adrenocortical† Tuberculosis Agents† Vitamins† |
| Specific Drugs Reported | |||
| also: diet high in vitamin K unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported. |
|||
| alcohol† aminoglutethimide amobarbital atorvastatin† azathioprine butabarbital butalbital carbamazepine chloral hydrate† chlordiazepoxide chlorthalidone |
cholestyramine† clozapine corticotropin cortisone cyclophosphamide† dicloxacillin ethchlorvynol glutethimide griseofulvin haloperidol meprobamate |
6-mercaptopurine methimazole† moricizine hydrochloride† nafcillin paraldehyde pentobarbital phenobarbital phenytoin† pravastatin† prednisone† primidone |
propylthiouracil† raloxifene ranitidine† rifampin secobarbital spironolactone sucralfate trazodone vitamin C (high dose) vitamin K warfarin underdosage |
| blood dyscrasias - see cancer collagen vascular disease congestive heart failure
|
diarrhea elevated temperature hepatic disorders infectious hepatitis jaundice
|
hyperthyroidism poor nutritional state steatorrhea vitamin K deficiency
|
| Classes of Drugs | |||
| 5-lipoxygenase Inhibitor Adrenergic Stimulants, Central Alcohol Abuse Reduction Preparations Analgesics Anesthetics, Inhalation Antiandrogen Antiarrhythmics† Antibiotics† Aminoglycosides (oral) Cephalosporins, parenteral Macrolides Miscellaneous Penicillins, intravenous, high dose Quinolones (fluoroquinolones) Sulfonamides, long acting Tetracyclines Anticoagulants Anticonvulsants† Antidepressants† Antimalarial Agents Antineoplastics† Antiparasitic/Antimicrobials
|
Antiplatelet Drugs/Effects Antithyroid Drugs† Beta-Adrenergic Blockers Cholelitholytic Agents Diabetes Agents, Oral Diuretics† Fungal Medications, Intravaginal, Systemic† Gastric Acidity and Peptic Ulcer Agents† Gastrointestinal Prokinetic Agents Ulcerative Colitis Agents Gout Treatment Agents Hemorrheologic Agents Hepatotoxic Drugs Hyperglycemic Agents Hypertensive Emergency Agents Hypnotics† Hypolipidemics† Bile Acid-Binding Resins† Fibric Acid Derivatives HMG-CoA Reductase Inhibitors†
|
Leukotriene Receptor Antagonist Monoamine Oxidase Inhibitors Narcotics, prolonged Nonsteroidal Anti- Inflammatory Agents Proton Pump Inhibitors Psychostimulants Pyrazolones Salicylates Selective Serotonin Reuptake Inhibitors Steroids, Adrenocortical† Steroids, Anabolic (17-Alkyl Testosterone Derivatives) Thrombolytics Thyroid Drugs Tuberculosis Agents† Uricosuric Agents Vaccines Vitamins†
|
|
| Specific Drugs Reported | |||
| also: other medications affecting blood elements which may modify hemostasis dietary deficiencies prolonged hot weather unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported.
|
|||
| acetaminophen alcohol† allopurinol aminosalicylic acid amiodarone HCl argatroban aspirin atenolol atorvastatin† azithromycin bivalirudin capecitabine cefamandole cefazolin cefoperazone cefotetan cefoxitin ceftriaxone celecoxib cerivastatin chenodiol chloramphenicol chloral hydrate† chlorpropamide cholestyramine† cimetidine ciprofloxacin cisapride clarithromycin clofibrate cyclophosphamide† danazol dextran dextrothyroxine diazoxide
|
diclofenac dicumarol diflunisal disulfiram doxycycline erythromycin esomeprazole ethacrynic acid ezetimibe fenofibrate fenoprofen fluconazole fluorouracil fluoxetine flutamide fluvastatin fluvoxamine gefitinib gemifibrozil glucagon halothane heparin ibuprofen ifosfamide indomethacin influenza virus vaccine itraconazole ketoprofen ketorolac lansoprazole lepirudin levamisole levofloxacin levothyroxine liothyronine
|
lovastatin mefenamic acid methimazole† methyldopa methylphenidate methylsalicylate ointment (topical) metronidazole miconazole (intravaginal, oral, systemic) moricizine hydrochloride† nalidixic acid naproxen neomycin norfloxacin ofloxacin olsalazine omeprazole oxandrolone oxaprozin oxymetholone pantoprazole paroxetine penicillin G, intravenous pentoxifylline phenylbutazone phenytoin† piperacillin piroxicam pravastatin† prednisone† propafenone
|
propoxyphene propranolol propylthiouracil† quinidine quinine rabeprazole ranitidine† rofecoxib sertraline simvastatin stanozolol streptokinase sulfamethizole sulfamethoxazole sulfinpyrazone sulfisoxazole sulindac tamoxifen tetracycline thyroid ticarcillin ticlopidine tissue plasminogen activator (t-PA) tolbutamide tramadol trimethoprim/ sulfamethoxazole urokinase valdecoxib valproate vitamin E warfarin overdose zafirlukast zileuton
|
| edema hereditary coumarin resistance hyperlipemia
|
hypothyroidism nephrotic syndrome
|
| Classes of Drugs | ||
| Adrenal Cortical Steroid Inhibitors Antacids Antianxiety Agents Antiarrhythmics† Antibiotics† Anticonvulsants† Antidepressants† Antihistamines Antineoplastics†
|
Antipsychotic Medications Antithyroid Drugs† Barbiturates Diuretics† Enteral Nutritional Supplements Fungal Medications, Systemic† Gastric Acidity and Peptic Ulcer Agents† Hypnotics†
|
Hypolipidemics† Bile Acid-Binding Resins† HMG-CoA Reductase Inhibitors† Immunosuppressives Oral Contraceptives, Estrogen Containing Selective Estrogen Receptor Modulators Steroids, Adrenocortical† Tuberculosis Agents† Vitamins†
|
| Specific Drugs Reported | |||
| also: diet high in vitamin K unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported.
|
|||
| alcohol† aminoglutethimide amobarbital atorvastatin† azathioprine butabarbital butalbital carbamazepine chloral hydrate† chlordiazepoxide chlorthalidone
|
cholestyramine† clozapine corticotropin cortisone cyclophosphamide† dicloxacillin ethchlorvynol glutethimide griseofulvin haloperidol meprobamate
|
6-mercaptopurine methimazole† moricizine hydrochloride† nafcillin paraldehyde pentobarbital phenobarbital phenytoin† pravastatin† prednisone† primidone
|
propylthiouracil† raloxifene ranitidine† rifampin secobarbital spironolactone sucralfate trazodone vitamin C (high dose) vitamin K warfarin underdosage
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| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1) |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2) |
| Antidiabetic agents | Carefully monitor blood glucose (5.11, 7.3) |
| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
| Interacting Drug | Interaction |
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
| Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) | VIAGRA 25 mg |
|---|---|
| Supine | 7.4 (-0.9, 15.7) |
| Standing | 6.0 (-0.8, 12.8) |
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| Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) | VIAGRA 100 mg |
|---|---|
| Supine | 7.9 (4.6, 11.1) |
| Standing |
4.3 (-1.8,10.3) |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
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| Amiodarone Iodide (including iodine- containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
|
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|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
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|
|||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
| |
|
| |
|
| Dopamine / Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day). |
| |
|
| |
|
| Aminoglutethimide Amiodarone Iodide(including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
| |
|
| Amiodarone Iodide(including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
| |
|
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
| |
|
| |
|
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
| |
|
| Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4, and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
| |
|
| |
|
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
| |
|
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
| |
|
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms. |
| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
|
|
|
||
|
|
|||
| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
|
|
|||
|
|
|||
| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
|
|
|||
|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
| |
|||
|
|
|
||
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
||
|
|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
| |
|||
| |
|||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
|
|
|||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
|
|
|||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine | Do not exceed 10 mg atorvastatin daily |
| Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir) | Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used. |
| Salmonella/Microsome Test (Negative) |
|
|
| Mouse Lymphoma Cell Forward Mutation Assay (Positive) |
| Chinese Hamster V79Cell HGPRT Test (Negative) |
| Syrian Hamster Embryo Cell Transformation Assay (Negative) |
|
|
|
|
| Rat Hepatocyte DNA Repair Assay (Positive) |
| Rat Hepatocyte DNA Repair Assay |
| Micronucleus Test (Mice) |
| Dominant Lethal Test (Mice) |
| AED Coadministered | AED Concentration | Topiramate Concentration |
| Phenytoin | NC or 25% increase |
48% decrease |
| Carbamazepine (CBZ) | NC | 40% decrease |
| CBZ epoxide |
NC | NE |
| Valproic acid | 11% decrease | 14% decrease |
| Phenobarbital | NC | NE |
| Primidone | NC | NE |
| Lamotrigine | NC at TPM doses up to 400 mg/day | 13% decrease |
| NC = Less than 10% change in plasma concentration. NE = Not Evaluated. |
||
|
|
|
||
|
|
|||
| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
|
|
|||
|
|
|||
| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
|
|
|||
|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
| |
|||
|
|
|
||
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
||
|
|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
| |
|||
| |
|||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
|
|
|||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
|
|
|||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
|
|
||
| AED Co-administered |
AED Concentration |
Topiramate Concentration |
| Phenytoin |
NC or 25% increasea
|
48% decrease |
| Carbamazepine (CBZ) |
NC |
40% decrease |
| CBZ epoxideb
|
NC |
NE |
| Valproic acid |
11% decrease |
14% decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NC at TPM doses up to 400 mg/day |
13% decrease |
| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of this product. |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding |
| Antidiabetic agents |
Carefully monitor blood glucose |
| Drug | Effect | Clinical Comment |
|---|---|---|
| ↑ Indicates increase. ↓ Indicates decrease. a The dosing recommendation for coadministration of didanosine delayed-release capsules and tenofovir disoproxil fumarate with respect to meal consumption differs from that of didanosine. See the complete prescribing information for didanosine delayed-release capsules. |
||
| ciprofloxacin |
↓ ciprofloxacin concentration |
Administer didanosine at least 2 hours after or 6 hours before ciprofloxacin. |
| delavirdine |
↓ delavirdine concentration |
Administer didanosine 1 hour after delavirdine. |
| ganciclovir |
↓ didanosine concentration |
If there is no suitable alternative to ganciclovir, then use in combination with didanosine with caution. Monitor for didanosine-associated toxicity. |
| indinavir |
↓ indinavir concentration |
Administer didanosine 1 hour after indinavir. |
| methadone |
↓ didanosine concentration |
Do not coadminister methadone with didanosine pediatric powder due to significant decreases in didanosine concentrations. If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is didanosine delayed-release capsules. Patients should be closely monitored for adequate clinical response when didanosine delayed-release capsules are coadministered with methadone, including monitoring for changes in HIV RNA viral load. |
| nelfinavir |
↓ No interacion 1 hour after didanosine |
Administer nelfinavir 1 hour after didanosine. |
| tenofovir disoproxil fumarate |
↓ didanosine concentration |
A dose reduction of didanosine to the following dosage once daily is recommended.a
|
| Drug or Drug Class | Effect | Clinical Comment |
|---|---|---|
| ↑ Indicates increase. ↓ Indicates decrease. a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of didanosine is recommended b |
||
| Drugs that may cause pancreatic toxicity |
↑ risk of pancreatitis |
Use only with extreme cautiona
|
| Neurotoxic drugs |
↑ risk of neuropathy |
Use with cautionb
|
| Antacids containing magnesium or aluminum |
↑ side effects associated with antacid components |
Use caution with Didanosine Pediatric Powder for Oral Solution |
| Azole antifungals |
↓ ketoconazole or Itraconazole concentration |
Administer drugs such as ketoconazole or itraconazole at least 2 hours before didanosine. |
| Quinolone antibiotics (see also ciprofloxacin in Table 8) |
↓ quinolone concentration |
Consult package insert of the quinolone. |
| Tetracycline antibiotics |
↓ antibiotic concentration |
Consult package insert of the tetracycline. |
|
|
|
| Amphetamines, cocaine, other sympathomimetic agents | Additive hypertension, tachycardia, possibly cardiotoxicity |
| Atropine, scopolamine, antihistamines, other anticholinergic agents | Additive or super-additive tachycardia, drowsiness |
| Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants | Additive tachycardia, hypertension, drowsiness |
| Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants | Additive drowsiness and CNS depression |
| Disulfiram | A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge |
| Fluoxetine | A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days |
| Antipyrine, barbiturates | Decreased clearance of these agents,presumably via competitive inhibition of metabolism |
| Theophylline | Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco |
|
|
|||||
| Coadministered Drug |
Dosing Schedule |
Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
Risperidone Dose Recommendation |
||
|
|
Coadministered Drug |
Risperidone |
AUC |
Cmax |
|
| Enzyme (CYP2D6) Inhibitors |
|
|
|
|
|
| Fluoxetine |
20 mg/day |
2 or 3 mg twice daily |
1.4 |
1.5 |
Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine |
10 mg/day |
4 mg/day |
1.3 |
|
Re-evaluate dosing. |
|
|
20 mg/day |
4 mg/day |
1.6 |
|
Do not exceed 8 mg/day |
|
|
40 mg/day |
4 mg/day |
1.8 |
|
|
| Enzyme (CYP3A/ PgP inducers) Inducers |
|
|
|
|
|
| Carbamazepine |
573 ± 168 mg/day |
3 mg twice daily |
0.51 |
0.55 |
Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors |
|
|
|
|
|
| Ranitidine |
150 mg twice daily |
1 mg single dose |
1.2 |
1.4 |
Dose adjustment not needed |
| Cimetidine |
400 mg twice daily |
1 mg single dose |
1.1 |
1.3 |
Dose adjustment not needed |
| Erythromycin |
500 mg four times daily |
1 mg single dose |
1.1 |
0.94 |
Dose adjustment not needed |
|
|
|
|
|
|
|
| Other Drugs |
|
|
|
|
|
| Amitriptyline |
50 mg twice daily |
3 mg twice daily |
1.2 |
1.1 |
Dose adjustment not needed |
| Concomitant Drug |
Effect on Concentration of Lamotrigine or Concomitant Drug |
Clinical Comment |
| Estrogen-containing oral Contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine ↓ levonorgestrel |
Decreased lamotrigine levelsapproximately 50%. Decrease in levonorgestrel component by 19%. |
| Carbamazepine and carbamazepine epoxide |
↓ lamotrigine ? CBZ epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels. |
| Phenobarbital/Primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40%. |
| Valproate |
↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
| Amphetamines, cocaine, other sympathomimetic agents | Additive hypertension, tachycardia, possibly cardiotoxicity |
| Atropine, scopolamine, antihistamines, other anticholinergic agents | Additive or super-additive tachycardia, drowsiness |
| Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants | Additive tachycardia, hypertension, drowsiness |
| Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants | Additive drowsiness and CNS depression |
| Disulfiram | A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge |
| Fluoxetine | A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days |
| Antipyrine, barbiturates | Decreased clearance of these agents, presumably via competitive inhibition of metabolism |
| Theophylline | Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco |
| Opioids | Cross-tolerance and mutual potentiation |
| Naltrexone | Oral THC effects were enhanced by opioid receptor blockade. |
| Alcohol | Increase in the positive subjective mood effects of smoked marijuana |
| * Refer to PRECAUTIONS, Drug Interactions for information regarding table. | |
| albuterol, systemic and inhaled | amoxicillin |
| ampicillin, with or without sulbactam | atenolol |
| azithromycin | caffeine, dietary ingestion |
| cefaclor | co-trimoxizole (trimethoprim and sulfamethoxazole) |
| diltiazem | dirithromycin |
| enflurane | famotidine |
| felodipine | finasteride |
| hydrocortisone | isoflurane |
| isoniazid | isradipine |
| influenza vaccine | ketoconazole |
| lomefloxacin | mebendazole |
| medroxyprogesterone | methylprednisolone |
| metronidazole | metoprolol |
| nadolol | nifedipine |
| nizatidine | norfloxacin |
| ofloxacin | omeprazole |
| prednisone, prednisolone | ranitidine |
| rifabutin | roxithromycin |
| sorbitol (purgative doses do not inhibit theophylline absorption) | sucralfate |
| terfenadine | terbutaline, systemic |
| tocainide | tetracycline |
|
|
|||||
|
|
|||||
| Dopamine / Dopamine Agonists | Glucocorticoids | Octreotide | |||
|
|
|||||
|
|
|||||
|
|
|||||
|
|
|||||
| Aminoglutethimide Amiodarone |
Iodide (including iodine-containing Radiographic contrast agents) Lithium |
Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
|||
|
|
|||||
|
|
|||||
|
|
|||||
| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
|||||
|
|
|||||
|
|
|||||
|
|
|||||
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone |
Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate |
Cation Exchange Resins - Kayexalate Ferrous Sulfate Sucralfate |
|||
|
|
|||||
|
|
|||||
|
|
|||||
| Clofibrate Estrogen-containing oral contraceptives |
Estrogens (oral) Heroin / Methadone 5-Fluorouracil |
Mitotane Tamoxifen |
|||
|
|
|||||
| Androgens / Anabolic Steroids | Glucocorticoids | ||||
| Asparaginase | Slow Release Nicotinic Acid | ||||
|
|
|||||
|
|
|||||
| Furosemide ( > 80 mg IV) Heparin Hydantoins |
Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
||||
|
|
|||||
|
|
|||||
|
|
|||||
|
|
|||||
| Carbamazepine | Hydantoins | Phenobarbital | Rifampin | ||
|
|
|||||
|
|
|||||
|
|
|||||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) |
Glucocorticoids - (e.g., Dexamethasone ≥4 mg/day) Propylthiouracil (PTU) |
||||
|
|
|||||
|
|
|||||
|
|
|||||
| Anticoagulants (oral) | |||||
| - Coumarin Derivatives | - Indandione Derivatives | ||||
|
|
|||||
|
|
|||||
| Antidepressants | |||||
| - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) |
- Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
||||
|
|
|||||
|
|
|||||
| Antidiabetic Agents - Biguanides |
- Meglitinides - Thiazolidinediones |
- Sulfonylureas - Insulin |
|||
|
|
|||||
|
|
|||||
| Cardiac Glycosides | |||||
|
|
|||||
|
|
|||||
| Cytokines | - Interferon-α | - Interleukin-2 | |||
|
|
|||||
|
|
|||||
| Growth Hormones | - Somatrem | - Somatropin | |||
|
|
|||||
|
|
|||||
| Ketamine | |||||
|
|
|||||
|
|
|||||
| Methylxanthine Bronchodilators - (e.g., Theophylline) | |||||
|
|
|||||
|
|
|||||
| Radiographic Agents | |||||
|
|
|||||
|
|
|||||
| Sympathomimetics | |||||
|
|
|||||
|
|
|||||
| Chloral Hydrate Diazepam Ethionamide Lovastatin |
Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium |
Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
|||
|
|
|||||
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
|
Decreased Lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide |
|
Addition of carbamazepine decreases Lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels. | |
| Phenobarbital/Primidone | ↓ Lamotrigine | Decreased Lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ Lamotrigine | Decreased Lamotrigine concentration approximately 40%. |
| Rifampin | ↓ Lamotrigine | Decreased Lamotrigine AUC approximately 40%. |
| Valproate |
|
Increased Lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
| albuterol, systemic and inhaled | felodipinefinasteride | nizatidinenorfloxacin |
| amoxicillin | hydrocortisone | ofloxacin |
| ampicillin, with or without sulbactam | isofluraneisoniazid | omeprazoleprednisone, prednisolone |
| atenolol | isradipine | ranitidine |
| azithromycin | influenza vaccine | rifabutin |
| caffeine, dietary ingestion | ketoconazolelomefloxacin | roxithromycinsorbitol |
| cefaclor | mebendazole | (purgative doses do not |
| co-trimoxazole (trimethoprim and sulfamethoxazole) | medroxyprogesteronemethylprednisolone | inhibit theophylline absorption) |
| diltiazem | metronidazole | sucralfate |
| dirithromycin | metoprolol | terbutaline, systemic |
| enflurane | nadolol | terfenadine |
| famotidine | nifedipine | tetracycline |
| tocainide | ||
| *Refer to | ||
| |
|
| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine,danazol | Do not exceed 10 mg simvastatindaily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Diltiazem | Do not exceed 40 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
| Interacting Agents | Prescribing Recommendations |
|---|---|
| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin |
| Verapamil, diltiazem |
Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine |
Do not exceed 20 mg simvastatin daily |
| Grapefruit juice |
Avoid large quantities of grapefruit juice (>1 quart daily) |
|
|
|
| Valproic acid | Doripenem reduced the serum concentrations of valproic acid to below the therapeutic concentration range in healthy subjects ( |
| Probenecid | Reduces renal clearance of doripenem, resulting in increased doripenem concentrations ( |
| Drugs metabolized by cytochrome P450 enzymes | Doripenem neither inhibits nor induces major cytochrome P450 enzymes ( |
| ↓ = Decreased (induces lamotrigine gluronidation). ↑ = Increased (inhibits lamotrigine glucuronidation). ? = Conflicting data. |
||
| Concomitant Drug |
Effect on Concentration of Lamotrigine or Concomitant Drug |
Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine ↓ levonorgestrel |
Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%. |
| Carbamazepine (CBZ) and CBZ epoxide |
↓ lamotrigine ? CBZ epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase CBZ epoxide levels |
| Phenobarbital/Primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40%. |
| Valproate |
↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
|
|
|
|
|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
|
|
|
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
| 1nc denotes a mean change of less than 10% | ||||
| 2Pediatrics | ||||
| 3Mean increase in adults at high doses of immediate-release oxcarbazepine | ||||
|
Coadministered (daily dose) |
Oxcarbazepine (daily dose) |
Oxcarbazepine on AED Concentration Mean Change [90% Confidence Interval] |
MHD Concentration (Mean Change, 90% Confidence Interval) |
|
| Carbamazepine (400 – 2000 mg) |
900 mg | nc |
40% decrease [CI: 17% decrease, 57% decrease] |
Consider initiating Oxtellar XR™ at a higher dose. Monitor and titrate dose to desired clinical effect (see |
| Phenobarbital (100 – 150 mg) |
600 – 1800 mg | 14% increase [CI: 2% increase, 24% increase] |
25% decrease [CI: 12% decrease, 51% decrease] |
|
| Phenytoin (250 – 500 mg) |
600 – 1800 >1200-2400 |
nc up to 40% increase [CI: 12% increase, 60% increase] |
30% decrease [CI: 3% decrease, 48% decrease] |
|
| Valproic Acid (400 – 2800 mg) |
600-1800 | nc |
18% decrease [CI: 13% decrease, 40% decrease] |
Monitor. Dose adjustment of Oxtellar XR™ may not be needed. |
| a) This table is not all inclusive. | ||
| b) In a study of 6 normal volunteers, a significant increase in tacrolimus oral bioavailability (14±5% vs. 30±8%) was observed with concomitant ketoconazole administration (200 mg). The apparent oral clearance of tacrolimus during ketoconazole administration was significantly decreased compared to tacrolimus alone (0.430±0.129 L/hr/kg vs. 0.148±0.043 L/hr/kg). Overall, IV clearance of tacrolimus was not significantly changed by ketoconazole coadministration, although it was highly variable between patients. | ||
| c) Lansoprazole (CYP2C19, CYP3A4 substrate) may potentially inhibit CYP3A4-mediated metabolism of tacrolimus and thereby substantially increase tacrolimus whole blood concentrations, especially in transplant patients who are intermediate or poor CYP2C19 metabolizers, as compared to those patients who are efficient CYP2C19 metabolizers. | ||
| Calcium | Antifungal | Macrolide |
| |
|
|
| diltiazem | clotrimazole | clarithromycin |
| nicardipine | fluconazole | erythromycin |
| nifedipine | itraconazole | troleandomycin |
| verapamil |
voriconazole |
|
| Gastrointestinal | Other | |
| |
|
|
| cisapride | bromocriptine | |
| metoclopramide | chloramphenicol | |
| cimetidine | ||
| cyclosporine | ||
| danazol | ||
| ethinyl estradiol | ||
| methylprednisolone | ||
| lansoprazolec | ||
| omeprazole | ||
| protease inhibitors | ||
| nefazodone | ||
| magnesium-aluminum-hydroxide | ||
| a) This table is not all inclusive. | |
| |
|
| carbamazepine | rifabutin |
| phenobarbital | caspofungin |
| phenytoin | rifampin |
| |
|
| St. John’s Wort | sirolimus |
|
|
|
|
|---|---|---|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|---|---|
|
|
|
|
|
|
|
|
|
|
|
|
| Enzyme | Inhibitors | Inducers |
|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
| Drug Class | Specific Drugs |
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
|
|
|
||
|
|
|||
| Dopamine/Dopamine Agonists Glucocorticoids Octreotide
|
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
|
|
|||
|
|
|||
| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide
|
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. 4 3 | ||
|
|
|||
| Amiodarone Iodide (including iodine- containing Radiographic contrast agents)
|
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
|
|
|||
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate
|
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
|
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|
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| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)
|
Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT , is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. 4 4 4 4 3 4 4 4 | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin
|
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. 4 | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)
|
Administration of these enzyme inhibitors decrease the peripheral conversion of T to T , Ieading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T and T levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). 4 3 3 4 3 4 3 4 3 4 | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives
|
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
|
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin
|
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2
|
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin
|
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline)
|
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of I, I, and Tc. 123 131 99m | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics
|
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
|
|
|
| Amiodarone Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
|
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|
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
|
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|
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
| Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
|
|
|
|
|
|
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
|
|
|
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
|
|
|
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
|
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|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
|
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|
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
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|---|---|
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|---|---|---|
| Erythromycin (500 mg every 8 hrs) |
+82% | +109% |
| Ketoconazole (400 mg once daily) |
+135% | +164% |
| DRUG | DISCRIPTION OF INTERACTION |
|---|---|
| Sulfonylureas | Hypoglycemia potentiated |
| Methotrexate | Decreases tubular reabsorption; clinical toxicity from methotrexate can result. |
| Oral Anticoagulants | Increased bleeding |
| DRUG | DISCRIPTION OF INTERACTION |
|---|---|
| Corticosteroids | Decreases plasma salicylate level; tapering doses of steroids may promote salicylism. |
| Acidifying agents | Increases plasma salicylate levels. |
| Alkcanizing agents | Decreased plasma salicylate levels. |
| DRUG | DISCRIPTION OF INTERACTION |
|---|---|
| Heparin | Salicylate decreases platelet adhesiveness and inteferes with hemostasis in heparin treated patients. |
| Pyrazinamide | Inhibits pyrazinamide induced hyperuricemia. |
| Uricosuric Agents | Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited. |
| Drug/Drug Class (Mechanism of Interaction by the Drug) |
Voriconazole Plasma Exposure (Cmax and AUCτ after 200 mg Q12h) |
Recommendations for Voriconazole Dosage Adjustment/Comments |
| Rifampin (CYP450 Induction) |
Significantly Reduced |
|
| Efavirenz (CYP450 Induction) |
Significantly Reduced | When voriconazole is coadministered with efavirenz, voriconazole maintenance dose should be increased to 400 mg Q12h and efavirenz should be decreased to 300 mg Q24h (See |
| High-dose Ritonavir (400mg Q12h) (CYP450 Induction) |
Significantly Reduced |
|
| Low-dose Ritonavir (100mg Q12h) (CYP450 Induction) |
Reduced | Coadministration of voriconazole and low-dose ritonavir (100 mg Q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole |
| Carbamazepine (CYP450 Induction) |
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction |
|
| Long Acting Barbiturates (CYP450 Induction) |
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction |
|
| Phenytoin (CYP450 Induction) |
Significantly Reduced | Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV every 12 hrs or from 200 mg to 400 mg orally every 12 hrs (100 mg to 200 mg orally every 12 hrs in patients weighing less than 40 kg) |
| St. John's Wort (CYP450 inducer; P-gp inducer) |
Significantly Reduced |
|
| Oral Contraceptives |
Increased | Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives |
| Other HIV Protease Inhibitors (CYP3A4 Inhibition) |
In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure) |
No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors |
| Other NNRTIs (CYP3A4 Inhibition or CYP450 Induction) |
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure) | Frequent monitoring for adverse events and toxicity related to voriconazole |
|
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure) |
Careful assessment of voriconazole effectiveness |
| Drug/Drug Class (Mechanism of Interaction by Voriconazole) |
Drug Plasma Exposure (Cmax and AUCτ) |
Recommendations for Drug Dosage Adjustment/Comments |
| Sirolimus (CYP3A4 Inhibition) |
Significantly Increased |
|
| Rifabutin (CYP3A4 Inhibition) |
Significantly Increased |
|
| Efavirenz (CYP3A4 Inhibition) |
Significantly Increased | When voriconazole is coadministered with efavirenz, voriconazole maintenance dose should be increased to 400 mg Q12h and efavirenz should be decreased to 300 mg Q24h (See |
| High-dose Ritonavir (400 mg Q12h) |
No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ |
|
| Low-dose Ritonavir (100mg Q12h) |
Slight Decrease in Ritonavir Cmax and AUCτ | Coadministration of voriconazole and low-dose ritonavir (100 mg Q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole |
| Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition) |
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased |
|
| Ergot Alkaloids (CYP450 Inhibition) |
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased |
|
| Cyclosporine (CYP3A4 Inhibition) |
AUCτ Significantly Increased; No Significant Effect on Cmax | When initiating therapy with VFEND in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary. |
| Methadone |
Increased | Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed |
| Alfentanil (CYP3A4 Inhibition) | Significantly Increased | Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary (see |
| Tacrolimus (CYP3A4 Inhibition) |
Significantly Increased | When initiating therapy with VFEND in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary. |
| Phenytoin (CYP2C9 Inhibition) |
Significantly Increased | Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin. |
| Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition) |
Increased | Monitoring for adverse events related to oral contraceptives is recommended during coadministration. |
| Warfarin (CYP2C9 Inhibition) |
Prothrombin Time Significantly Increased | Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed. |
| Omeprazole (CYP2C19/3A4 Inhibition) |
Significantly Increased | When initiating therapy with VFEND in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors. |
| Other HIV Protease Inhibitors (CYP3A4 Inhibition) |
In Vivo Studies Showed No Significant Effects on Indinavir Exposure In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) |
No dosage adjustment for indinavir when coadministered with VFEND Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors |
| Other NNRTIs (CYP3A4 Inhibition) |
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to NNRTI |
| Benzodiazepines (CYP3A4 Inhibition) |
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed. |
| HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition) |
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed. |
| Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition) |
In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed. |
| Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition) |
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased | Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed. |
| Vinca Alkaloids (CYP3A4 Inhibition) |
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased | Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed. |
| AED Co-administered | AED Concentration | Topiramate Concentration |
| Phenytoin |
NC or 25% increasea | 48% decrease |
| Carbamazepine (CBZ) | NC |
40% decrease |
| CBZ epoxideb | NC |
NE |
| Valproic acid |
11% decrease | 14% decrease |
| Phenobarbital | NC | NE |
| Primidone |
NC | NE |
| Lamotrigine |
NC at TPM doses up to 400 mg/day | 13% decrease |
|
|
|
| Acetaminophen, caffeine, imipramine, oxazepam, pentazocine, propranolol, or other beta-blockers, theophylline | Deinduction of hepatic enzymes on smoking cessation. |
| Insulin | Increase of subcutaneous insulin absorption with smoking cessation. |
| Adrenergic antagonists (e.g. prazosin, labetalol) | Decrease in circulating catecholamines with smoking cessation. |
|
|
|
| Adrenergic agonists (e.g. isoproterenol, phenylephrine) | Decrease in circulating catecholamines with smoking cessation. |
|
|
|
|
e.g., |
|
|
e.g., tri-iodothyronine |
2 weeks |
|
|
2 weeks |
|
|
|
|
|
|
|
corticosteroids, sulfonamides tolbutamide, perchlorate phenylbutazone lithium |
1 week 1 week 1-2 weeks 4 weeks |
| Concomitant Drug Class: Drug Name |
Effect on Concentration of Darunavir or Concomitant Drug | Clinical Comment |
|---|---|---|
|
|
||
| didanosine | ↔ darunavir ↔ didanosine |
Didanosine should be administered one hour before or two hours after PREZISTA/ritonavir (which are administered with food). |
|
|
||
| indinavir (The reference regimen for indinavir was indinavir/ritonavir 800/100 mg twice daily.) |
↑ darunavir ↑ indinavir |
The appropriate dose of indinavir in combination with PREZISTA/ritonavir has not been established. |
| lopinavir/ritonavir | ↓ darunavir ↔ lopinavir |
Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer lopinavir/ritonavir and PREZISTA, with or without ritonavir. |
| saquinavir | ↓ darunavir ↔ saquinavir |
Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer saquinavir and PREZISTA, with or without ritonavir. |
|
|
||
| maraviroc | ↑ maraviroc | Maraviroc concentrations are increased when co-administered with PREZISTA/ritonavir. When used in combination with PREZISTA/ritonavir, the dose of maraviroc should be 150 mg twice daily. |
|
|
||
|
bepridil, lidocaine (systemic), quinidine, amiodarone, flecainide, propafenone |
↑ antiarrhythmics | Concentrations of these drugs may be increased when co-administered with PREZISTA/ritonavir. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when co-administered with PREZISTA/ritonavir. |
| digoxin | ↑ digoxin | The lowest dose of digoxin should initially be prescribed. The serum digoxin concentrations should be monitored and used for titration of digoxin dose to obtain the desired clinical effect. |
|
warfarin |
↓ warfarin ↔ darunavir |
Warfarin concentrations are decreased when co-administered with PREZISTA/ritonavir. It is recommended that the international normalized ratio (INR) be monitored when warfarin is combined with PREZISTA/ritonavir. |
|
carbamazepine |
↔ darunavir ↑ carbamazepine |
The dose of either darunavir/ritonavir or carbamazepine does not need to be adjusted when initiating co-administration with darunavir/ritonavir and carbamazepine. Clinical monitoring of carbamazepine concentrations and its dose titration is recommended to achieve the desired clinical response. |
|
phenobarbital, phenytoin |
↔ darunavir ↓ phenytoin ↓ phenobarbital |
Co-administration of PREZISTA/ritonavir may cause a decrease in the steady-state concentrations of phenytoin and phenobarbital. Phenytoin and phenobarbital levels should be monitored when co-administering with PREZISTA/ritonavir. |
|
trazodone, desipramine |
↑ trazodone ↑ desipramine |
Concomitant use of trazodone or desipramine and PREZISTA/ritonavir may increase plasma concentrations of trazodone or desipramine which may lead to adverse events such as nausea, dizziness, hypotension and syncope. If trazodone or desipramine is used with PREZISTA/ritonavir, the combination should be used with caution, and a lower dose of trazodone or desipramine should be considered. |
|
clarithromycin |
↔ darunavir ↑ clarithromycin |
No dose adjustment of the combination is required for patients with normal renal function. For patients with renal impairment, the following dose adjustments should be considered:
|
|
ketoconazole, itraconazole, voriconazole |
↑ ketoconazole ↑ darunavir ↑ itraconazole (not studied) ↓ voriconazole (not studied) |
Ketoconazole and itraconazole are potent inhibitors as well as substrates of CYP3A. Concomitant systemic use of ketoconazole, itraconazole, and darunavir/ritonavir may increase plasma concentration of darunavir. |
| Plasma concentrations of ketoconazole or itraconazole may be increased in the presence of darunavir/ritonavir. When co-administration is required, the daily dose of ketoconazole or itraconazole should not exceed 200 mg. | ||
| Plasma concentrations of voriconazole may be decreased in the presence of darunavir/ritonavir. Voriconazole should not be administered to patients receiving darunavir/ritonavir unless an assessment of the benefit/risk ratio justifies the use of voriconazole. | ||
|
colchicine |
↑ colchicine |
0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days. If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Patients with renal or hepatic impairment should not be given colchicine with PREZISTA/ritonavir. |
|
artemether/lumefantrine |
↓ artemether ↓ dihydroartemisinin ↑ lumefantrine ↔ darunavir |
The combination of PREZISTA and artemether/lumefantrine can be used without dose adjustments. However, the combination should be used with caution as increased lumefantrine exposure may increase the risk of QT prolongation. |
|
rifabutin |
↑ darunavir ↑ rifabutin ↑ 25- |
Dose reduction of rifabutin by at least 75% of the usual dose (300 mg once daily) is recommended (i.e., a maximum dose of 150 mg every other day). Increased monitoring for adverse events is warranted in patients receiving this combination and further dose reduction of rifabutin may be necessary. |
| The reference regimen for rifabutin was 300 mg once daily | ||
|
metoprolol, timolol |
↑ beta-blockers | Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir. |
|
parenterally administered midazolam |
↑ midazolam | Concomitant use of parenteral midazolam with PREZISTA/ritonavir may increase plasma concentrations of midazolam. Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Co-administration of oral midazolam with PREZISTA/ritonavir is CONTRAINDICATED. |
|
felodipine, nifedipine, nicardipine |
↑ calcium channel blockers | Plasma concentrations of calcium channel blockers (e.g., felodipine, nifedipine, nicardipine) may increase when PREZISTA/ritonavir are co-administered. Caution is warranted and clinical monitoring of patients is recommended. |
|
dexamethasone |
↓ darunavir | Systemic dexamethasone induces CYP3A and can thereby decrease darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA. |
|
fluticasone |
↑ fluticasone | Concomitant use of inhaled fluticasone and PREZISTA/ritonavir may increase plasma concentrations of fluticasone. Alternatives should be considered, particularly for long-term use. |
|
bosentan |
↑ bosentan |
In patients who have been receiving PREZISTA/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of PREZISTA/ritonavir. After at least 10 days following the initiation of PREZISTA/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. |
|
NS3-4A protease inhibitors: boceprevir telaprevir |
↓ darunavir ↓ boceprevir ↓ telaprevir |
|
|
pravastatin, atorvastatin, rosuvastatin |
↑ pravastatin ↑ atorvastatin ↑ rosuvastatin |
Titrate atorvastatin, pravastatin or rosuvastatin dose carefully and use the lowest necessary dose while monitoring for safety. Do not exceed atorvastatin 20 mg/day. |
|
cyclosporine, tacrolimus, sirolimus |
↑ immunosuppressants | Plasma concentrations of cyclosporine, tacrolimus or sirolimus may be increased when co-administered with PREZISTA/ritonavir. Therapeutic concentration monitoring of the immunosuppressive agent is recommended when co-administered with PREZISTA/ritonavir. |
|
salmeterol |
↑ salmeterol | Concurrent administration of salmeterol and PREZISTA/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
|
methadone, buprenorphine, buprenorphine/naloxone |
↓ methadone ↔ buprenorphine, naloxone ↑ norbuprenorphine (metabolite) |
No adjustment of methadone dosage is required when initiating co-administration of PREZISTA/ritonavir. However, clinical monitoring is recommended as the dose of methadone during maintenance therapy may need to be adjusted in some patients. No dose adjustment for buprenorphine or buprenorphine/naloxone is required with concurrent administration of PREZISTA/ritonavir. Clinical monitoring is recommended if PREZISTA/ritonavir and buprenorphine or buprenorphine/naloxone are coadministered. |
|
risperidone, thioridazine |
↑ neuroleptics | A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir. |
|
ethinyl estradiol, norethindrone |
↓ ethinyl estradiol ↓ norethindrone |
Plasma concentrations of ethinyl estradiol are decreased due to induction of its metabolism by ritonavir. Alternative methods of nonhormonal contraception are recommended. |
|
sildenafil, vardenafil, tadalafil |
↑ PDE-5 inhibitors (only the use of sildenafil at doses used for treatment of erectile dysfunction has been studied with PREZISTA/ritonavir) |
Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg dose in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours can be used with increased monitoring for PDE-5 inhibitor-associated adverse events. |
|
sertraline, paroxetine |
↔ darunavir ↓ sertraline ↓ paroxetine |
If sertraline or paroxetine is co-administered with PREZISTA/ritonavir, the recommended approach is a careful dose titration of the SSRI based on a clinical assessment of antidepressant response. In addition, patients on a stable dose of sertraline or paroxetine who start treatment with PREZISTA/ritonavir should be monitored for antidepressant response. |
|
|
Mean (±SD) |
| Bioavailability | 63% (34 to 108%) |
| Clearance (mL/min) | 165 (55) |
| Volume of Distribution (L) | 76 (14) |
| Half-Life (hours) | 6.2 (2.1) |
|
|
Mean (± SD) | |
|
|
45 to 60 years old (n=12) | ≥70 years old (n=12) |
| AUC (ng |
389 (98) | 463 (186) |
| Peak Concentration (ng/mL) | 46.2 (8.7) | 48.4 (14.7) |
| Time to Peak (hours) | 1.8 (0.7) | 1.8 (0.6) |
| Half-Life (hours) |
6.0 (1.5) | 8.2 (2.5) |
| Concomitant Drug Class: Drug Name | Effect on Concentration of Boceprevir or Concomitant Drug | Recommendations |
|---|---|---|
| Antiarrhythmics: amiodarone, bepridil, propafenone, quinidine |
↑ antiarrhythmics |
Coadministration with VICTRELIS has the potential to produce serious and/or life-threatening adverse events and has not been studied. Caution is warranted and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with VICTRELIS. |
| digoxin |
↑ digoxin | Digoxin concentrations increased when administered with VICTRELIS |
| Anticoagulant: warfarin | ↑ or ↓ warfarin | Concentrations of warfarin may be altered when co-administered with VICTRELIS. Monitor INR closely. |
| Antidepressants: trazodone, desipramine | ↑ trazodone ↑ desipramine |
Plasma concentrations of trazodone and desipramine may increase when administered with VICTRELIS, resulting in adverse events such as dizziness, hypotension and syncope. Use with caution and consider a lower dose of trazodone or desipramine. |
| escitalopram |
↓escitalopram | Exposure of escitalopram was slightly decreased when coadministered with VICTRELIS. Selective serotonin reuptake inhibitors such as escitalopram have a wide therapeutic index, but doses may need to be adjusted when combined with VICTRELIS. |
| Antifungals: ketoconazole |
↑ boceprevir ↑ itraconazole ↑ ketoconazole ↑ posaconazole ↑ voriconazole |
Plasma concentrations of ketoconazole, itraconazole, voriconazole or posaconazole may be increased with VICTRELIS. When coadministration is required, doses of ketoconazole and itraconazole should not exceed 200 mg/day. |
| Anti-gout: colchicine | ↑ colchicine | Significant increases in colchicine levels are expected; fatal colchicine toxicity has been reported with other strong CYP3A4 inhibitors. Patients with renal or hepatic impairment should not be given colchicine with VICTRELIS. Treatment of gout flares (during treatment with VICTRELIS): 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares (during treatment with VICTRELIS): If the original regimen was 0.6 mg twice a day, reduce dose to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, reduce the dose to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF) (during treatment with VICTRELIS): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). |
| Anti-infective: clarithromycin | ↑ clarithromycin | Concentrations of clarithromycin may be increased with VICTRELIS; however, no dosage adjustment is necessary for patients with normal renal function. |
| Antimycobacterial: rifabutin |
↓ boceprevir ↑ rifabutin |
Increases in rifabutin exposure are anticipated, while exposure of boceprevir may be decreased. Doses have not been established for the 2 drugs when used in combination. Concomitant use is not recommended. |
| Calcium Channel Blockers, dihydropyridine: felodipine, nifedipine, nicardipine | ↑ dihydropyridine calcium channel blockers | Plasma concentrations of dihydropyridine calcium channel blockers may increase when administered with VICTRELIS. Caution is warranted and clinical monitoring is recommended. |
| Corticosteroid, systemic: dexamethasone | ↓ boceprevir | Coadministration of VICTRELIS with CYP3A4/5 inducers may decrease plasma concentrations of boceprevir, which may result in loss of therapeutic effect. Therefore, this combination should be avoided if possible and used with caution if necessary. |
| prednisone |
↑ prednisone | Concentrations of prednisone and its active metabolite, prednisolone, increased when administered with VICTRELIS |
| Corticosteroid, inhaled: budesonide, fluticasone | ↑ budesonide ↑ fluticasone |
Concomitant use of inhaled budesonide or fluticasone with VICTRELIS may result in increased plasma concentrations of budesonide or fluticasone, resulting in significantly reduced serum cortisol concentrations. Avoid coadministration if possible, particularly for extended durations. |
| Endothelin Receptor Antagonist: bosentan | ↑ bosentan | Concentrations of bosentan may be increased when coadministered with VICTRELIS. Use with caution and monitor closely. |
| HIV Integrase Inhibitor: raltegravir |
↔ raltegravir | No dose adjustment required for VICTRELIS or raltegravir. |
| HIV Non-Nucleoside Reverse Transcriptase Inhibitors: efavirenz |
↓ boceprevir | Plasma trough concentrations of boceprevir were decreased when VICTRELIS was coadministered with efavirenz, which may result in loss of therapeutic effect. Avoid combination. |
| etravirine |
↓ etravirine | Concentrations of etravirine decreased when coadministered with VICTRELIS. The clinical significance of the reductions in etravirine pharmacokinetic parameters has not been directly assessed. |
| HIV Protease Inhibitors: atazanavir/ritonavir |
↓ atazanavir ↓ ritonavir |
Concomitant administration of boceprevir and atazanavir/ritonavir resulted in reduced steady-state exposures to atazanavir and ritonavir. Coadministration of atazanavir/ritonavir and boceprevir is not recommended. |
| darunavir/ritonavir |
↓ darunavir ↓ ritonavir ↓ boceprevir |
Concomitant administration of boceprevir and darunavir/ritonavir resulted in reduced steady-state exposures to boceprevir, darunavir and ritonavir. Coadministration of darunavir/ritonavir and boceprevir is not recommended. |
| lopinavir/ritonavir |
↓ lopinavir ↓ ritonavir ↓ boceprevir |
Concomitant administration of boceprevir and lopinavir/ritonavir resulted in reduced steady-state exposures to boceprevir, lopinavir and ritonavir. Coadministration of lopinavir/ritonavir and boceprevir is not recommended. |
| ritonavir |
↓ boceprevir | When boceprevir is administered with ritonavir alone, boceprevir concentrations are decreased. |
| HMG-CoA Reductase Inhibitors: atorvastatin |
↑ atorvastatin | Exposure to atorvastatin was increased when administered with VICTRELIS. Use the lowest effective dose of atorvastatin, but do not exceed a daily dose of 40 mg when coadministered with VICTRELIS. |
| pravastatin |
↑ pravastatin | Concomitant administration of pravastatin with VICTRELIS increased exposure to pravastatin. Treatment with pravastatin can be initiated at the recommended dose when coadministered with VICTRELIS. Close clinical monitoring is warranted. |
| Immunosuppressants: cyclosporine |
↑cyclosporine |
Dose adjustments of cyclosporine should be anticipated when administered with VICTRELIS and should be guided by close monitoring of cyclosporine blood concentrations, and frequent assessments of renal function and cyclosporine-related side effects. |
| ↑tacrolimus |
Concomitant administration of VICTRELIS with tacrolimus requires significant dose reduction and prolongation of the dosing interval for tacrolimus, with close monitoring of tacrolimus blood concentrations and frequent assessments of renal function and tacrolimus-related side effects. |
|
| ↑sirolimus |
Blood concentrations of sirolimus are expected to increase significantly when administered with VICTRELIS. Close monitoring of sirolimus blood levels is recommended. | |
| Inhaled beta-agonist: salmeterol | ↑ salmeterol | Concurrent use of inhaled salmeterol and VICTRELIS is not recommended due to the risk of cardiovascular events associated with salmeterol. |
| Narcotic Analgesic/Opioid Dependence: methadone |
↓ R-methadone | Plasma concentrations of |
| buprenorphine/naloxone |
↑ buprenorphine/naloxone | Plasma concentrations of buprenorphine and naloxone increased when coadministered with VICTRELIS |
| Oral hormonal contraceptives: drospirenone/ethinyl estradiol |
↑ drospirenone ↓ ethinyl estradiol |
Concentrations of drospirenone increased in the presence of boceprevir. Thus, the use of drospirenone-containing products is contraindicated during treatment with VICTRELIS due to potential for hyperkalemia |
| norethindrone/ethinyl estradiol |
↓ ethinyl estradiol ↔ norethindrone |
Concentrations of ethinyl estradiol decreased in the presence of boceprevir. Norethindrone Cmax decreased 17% in the presence of boceprevir Patients using estrogens as hormone replacement therapy should be clinically monitored for signs of estrogen deficiency. |
| PDE5 inhibitors: sildenafil, tadalafil, vardenafil | ↑ sildenafil ↑ tadalafil ↑ vardenafil |
Increases in PDE5 inhibitor concentrations are expected, and may result in an increase in adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of REVATIO® (sildenafil) or ADCIRCA® (tadalafil) for the treatment of pulmonary arterial hypertension (PAH) is contraindicated with VICTRELIS Use with caution in combination with VICTRELIS with increased monitoring for PDE5 inhibitor-associated adverse events. Do not exceed the following doses: Sildenafil: 25 mg every 48 hours Tadalafil: 10 mg every 72 hours Vardenafil: 2.5 mg every 24 hours |
| Proton Pump Inhibitor: omeprazole |
↔ omeprazole | No dose adjustment of omeprazole or VICTRELIS is recommended. |
| Sedative/hypnotics: alprazolam; IV midazolam | ↑ midazolam ↑ alprazolam |
Close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised during coadministration of VICTRELIS. A lower dose of IV midazolam or alprazolam should be considered. |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
|
Decreased Lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide |
|
Addition of carbamazepine decreases Lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels. | |
| Phenobarbital/Primidone | ↓ Lamotrigine | Decreased Lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ Lamotrigine | Decreased Lamotrigine concentration approximately 40%. |
| Rifampin | ↓ Lamotrigine | Decreased Lamotrigine AUC approximately 40%. |
| Valproate |
|
Increased Lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
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|
Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
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|
Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
|
|
|
|
Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
|
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|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function. |
|
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|
Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
|
Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4 . Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
|
|
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|
|
Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
|
|
|
|
Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
|
|
|
|
- Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
|
- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
|
- Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
|
- Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
|
- Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
|
- (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
|
Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
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||
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|
|
+82% | +109% |
|
|
+135% | +164% |
|
|
|
| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, gemfibrozil, cyclosporine,danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid grapefruit juice |
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) | Do not exceed 40 mg atorvastatin daily |
| Concomitant Drug Class: Drug Name |
Effect on Concentration of Raltegravir | Clinical Comment |
|---|---|---|
|
|
||
| atazanavir | ↑ | Atazanavir, a strong inhibitor of UGT1A1, increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended. |
| atazanavir/ritonavir | ↑ | Atazanavir/ritonavir increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended. |
| efavirenz | ↓ | Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed. |
| etravirine | ↓ | Etravirine reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed. |
| tipranavir/ritonavir | ↓ | Tipranavir/ritonavir reduces plasma concentrations of raltegravir. However, since comparable efficacy was observed for this combination relative to other ISENTRESS-containing regimens in Phase 3 studies 018 and 019, no dose adjustment is recommended. |
|
|
||
| omeprazole | ↑ | Coadministration of medicinal products that increase gastric pH (e.g., omeprazole) may increase raltegravir levels based on increased raltegravir solubility at higher pH. However, since concomitant use of ISENTRESS with proton pump inhibitors and H2 blockers did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended. |
| rifampin | ↓ | Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of raltegravir. The recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin. |
| Interaction Drug | Interaction |
|---|---|
| Rifabutin, phenytoin, efavirenz, cimetidine, esomeprazole | Avoid coadministration unless the benefit outweighs the risks ( |
| Other drugs metabolized by CYP3A4 (tacrolimus, cyclosporine, vinca alkaloids, calcium channel blockers) | Consider dosage adjustment and monitor for adverse effects and toxicity ( |
| Digoxin | Monitor digoxin plasma concentrations ( |
| Fosamprenavir, metoclopramide | Monitor for breakthrough fungal infections ( |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
|
Decreased Lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide |
|
Addition of carbamazepine decreases Lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels. | |
| Phenobarbital/Primidone | ↓ Lamotrigine | Decreased Lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ Lamotrigine | Decreased Lamotrigine concentration approximately 40%. |
| Rifampin | ↓ Lamotrigine | Decreased Lamotrigine AUC approximately 40%. |
| Valproate |
|
Increased Lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
|
|
|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
| DRUG | EFFECT |
|---|---|
| Monoamine Oxidase (MAO) Inhibitors |
Hypertension |
| Enzyme | Inhibitors | Inducers |
|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
| Drug Class | Specific Drugs |
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
|
|
|
| Itraconazole, ketoconazole, Posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine,danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
|
|
|
| Itraconazole, ketoconazole, Posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine,danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
| Drug | Effect | |
|---|---|---|
| Phenylephrine with prior administration of monoamine oxidase inhibitors (MAOI). |
Cardiac pressor response potentiated. May cause acute hypertensive crisis. |
|
| Phenylephrine with tricyclic anti-depressants. |
Pressor response increased. |
|
| Phenylephrine with ergot alkaloids. |
Excessive rise in blood pressure. |
|
| Phenylephrine with bronchodilator sympathomimetic agents and with epinephrine or other sympathomimetics. |
Tachycardia or other arrhythmias may occur. | |
| Phenylephrine with prior administration of propranolol or other β-adrenergic blockers. |
Cardiostimulating effects blocked. | |
| Phenylephrine with atropine sulfate. |
Reflex bradycardia blocked; pressor response enhanced. |
|
| Phenylephrine with prior administration of phentolamine or other α-adrenergic blockers. |
Pressor response decreased. | |
| Phenylephrine with diet preparations, such as amphetamines or phenylpropanolamine. |
Synergistic adrenergic response. |
|
|
|
| Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin |
| Amiodarone, verapamil, diltiazem |
Do not exceed 10 mg simvastatin daily |
| Amlodipine, ranolazine |
Do not exceed 20 mg simvastatin daily |
| Grapefruit juice |
Avoid large quantities of grapefruit juice (>1 quart daily) |
|
|
|
| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine, danazol | Do not exceed 10 mg simvastatin daily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
| Drug | Effect | Clinical Comment |
|---|---|---|
| ↑ Indicates increase. ↓ Indicates decrease. a Coadministration of didanosine with food decreases didanosine concentrations. Thus, although not studied, it is possible that coadministration with heavier meals could reduce didanosine concentrations further. |
||
|
ganciclovir |
↑ didanosine concentration |
If there is no suitable alternative to ganciclovir, then use in combination with didanosine delayed-release capsules with caution. Monitor for didanosine- associated toxicity. |
|
methadone |
↓ didanosine concentration |
If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is didanosine delayed-release capsules. Patients should be closely monitored for adequate clinical response when didanosine delayed-release capsules is coadministered with methadone, including monitoring for changes in HIV RNA viral load. Do not coadminister methadone with didanosine pediatric powder due to significant decreases in didanosine concentrations. |
|
nelfinavir |
No interaction 1 hour after didanosine |
Administer nelfinavir 1 hour after didanosine delayed-release capsules. |
|
tenofovir disoproxil fumarate |
↑ didanosine concentration |
A dose reduction of didanosine delayed-release capsules to the following dosage once daily taken together with tenofovir disoproxil fumarate and a light meal (400 kcalories or less and 20% fat or less) or in the fasted state is recommended.a
|
| Drug or Drug Class | Effect | Clinical Comment |
|---|---|---|
| ↑ Indicates increase. a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of didanosine delayed-release capsules b |
||
|
Drugs that may cause pancreatic toxicity |
↑ risk of pancreatitis |
Use only with extreme caution.a |
|
Neurotoxic drugs |
↑ risk of neuropathy |
Use with caution.b |
| Alpha-Blocker | Simultaneous dosing of Vardenafil 5 mg and Alpha-Blocker, Placebo-Subtracted |
Dosing of Vardenafil 5 mg and Alpha-Blocker Separated by 6 Hours, Placebo-Subtracted |
|
| Terazosin 5 or 10 mg daily |
Standing SBP | -3 (-6.7, 0.1) | -4 (-7.4, -0.5) |
| Supine SBP | -4 (-6.7, -0.5) | -4 (-7.1, -0.7) | |
| Tamsulosin 0.4 mg daily |
Standing SBP Supine SBP |
-6 (-9.9, -2.1) -4 (-7.0, -0.8) |
-4 (-8.3, -0.5) -5 (-7.9, -1.7) |
| Vardenafil 10 mg Placebo-subtracted |
Vardenafil 20 mg Placebo-subtracted |
|
| Standing SBP | -4 (-6.8, -0.3) | -4 (-6.8, -1.4) |
| Supine SBP | -5 (-8.2, -0.8) | -4 (-6.3, -1.8) |
|
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|
| Atazanavir/Ritonavir | ↓ Atazanavir ↑ Nevirapine |
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure. |
| Clarithromycin | ↓ Clarithromycin ↑ 14-OH clarithromycin |
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against |
| Efavirenz | ↓ Efavirenz | There has been no determination of appropriate doses for the safe and effective use of this combination [ |
| Ethinyl estradiol and Norethindrone | ↓ Ethinyl estradiol ↓ Norethindrone |
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended. |
| Fluconazole | ↑Nevirapine | Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events. |
| Fosamprenavir | ↓Amprenavir ↑Nevirapine |
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. |
| Fosamprenavir/Ritonavir | ↓Amprenavir ↑Nevirapine |
No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. |
| Indinavir | ↓ Indinavir | Appropriate doses for this combination are not established, but an increase in the dosage of indinavir may be required. |
| Ketoconazole | ↓ Ketoconazole | Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. |
| Lopinavir/Ritonavir | ↓Lopinavir | A dose increase of lopinavir/ritonavir tablets to 500/125 mg twice-daily is recommended when used in combination with nevirapine. A dose increase of lopinavir/ritonavir oral solution to 533/133 mg twice daily with food is recommended in combination with nevirapine. In children 6 months to 12 years of age receiving lopinavir/ritonavir solution, consideration should be given to increasing the dose of lopinavir/ritonavir to 13/3.25 mg/kg for those 7 to <15 kg; 11/2.75 mg/kg for those 15 to 45 kg; up to a maximum dose of 533/133 mg twice daily. Refer to the lopinavir/ritonavir package insert for complete pediatric dosing instructions when lopinavir/ritonavir tablets are used in combination with nevirapine. |
| Methadone | ↓ Methadone | Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. |
| Nelfinavir | ↓Nelfinavir M8 Metabolite ↓Nelfinavir Cmin |
The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established. |
| Rifabutin | ↑Rifabutin | Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. |
| Rifampin | ↓ Nevirapine | Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead. |
| Saquinavir/Ritonavir | The interaction between nevirapine and saquinavir/ritonavir has not been evaluated | The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established. |
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Examples of Drugs | |
|---|---|---|
| Antiarrhythmics | Amiodarone, disopyramide, lidocaine | Plasma concentrations may be decreased. |
| Anticonvulsants | Carbamazepine, clonazepam, ethosuximide | Plasma concentrations may be decreased. |
| Antifungals | Itraconazole | Plasma concentrations of some azole antifungals may be decreased. Nevirapine and itraconazole should not be administered concomitantly due to a potential decrease in itraconazole plasma concentrations. |
| Calcium channel blockers | Diltiazem, nifedipine, verapamil | Plasma concentrations may be decreased. |
| Cancer chemotherapy | Cyclophosphamide | Plasma concentrations may be decreased. |
| Ergot alkaloids | Ergotamine | Plasma concentrations may be decreased. |
| Immunosuppressants | Cyclosporin, tacrolimus, sirolimus | Plasma concentrations may be decreased. |
| Motility agents | Cisapride | Plasma concentrations may be decreased. |
| Opiate agonists | Fentanyl | Plasma concentrations may be decreased. |
| Antithrombotics | Warfarin | Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended. |
| albuterol, | famotidine | nizatidine |
| systemic and inhaled | felodipine | norfloxacin |
| amoxicillin | finasteride | ofloxacin |
| ampicillin, | hydrocortisone | omeprazole |
| with or without | isoflurane | prednisone, prednisolone |
| sulbactam | isoniazid | ranitidine |
| atenolol | isradipine | rifabutin |
| azithromycin | influenza vaccine | roxithromycin |
| caffeine, | ketoconazole | sorbitol |
| dietary ingestion | lomefloxacin | (purgative doses do not |
| cefaclor | mebendazole | inhibit theophylline |
| co-trimoxazole | medroxyprogesterone | absorption) |
| (trimethoprim and | methylprednisolone | sucralfate |
| sulfamethoxazole) | metronidazole | terbutaline, systemic |
| diltiazem | metoprolol | terfenadine |
| dirithromycin | nadolol | tetracycline |
| enflurane | nifedipine | tocainide |
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| Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | |
| Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | |
| Administration of these agents with levothyroxine results in an initial transient increase in FT4.Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | |
| Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | |
| Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | |
| Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | |
| Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | |
| Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients, and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and –γ have not been reported to cause thyroid dysfunction. | |
| Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
|---|---|---|
| ↓=Decreased (induces lamotrigine glucuronidation). ↑=Increased (inhibits lamotrigine glucuronidation). ?=Conflicting data. |
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| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine | Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide | ↓ lamotrigine | Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine | Increased lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. | |
| blood dyscrasias - see cancer collagen vascular disease congestive heart failure |
diarrhea elevated temperature hepatic disorders infectious hepatitis jaundice |
hyperthyroidism poor nutritional state steatorrhea vitamin K deficiency |
| Classes of Drugs | |||
| 5-lipoxygenase Inhibitor Adrenergic Stimulants, Central Alcohol Abuse Reduction Preparations Analgesics Anesthetics, Inhalation Antiandrogen Antiarrhythmics† Antibiotics† Aminoglycosides (oral) Cephalosporins, parenteral Macrolides Miscellaneous Penicillins, intravenous, high dose Quinolones (fluoroquinolones) Sulfonamides, long acting Tetracyclines Anticoagulants Anticonvulsants† Antidepressants† Antimalarial Agents Antineoplastics† Antiparasitic/Antimicrobials |
Antiplatelet Drugs/Effects Antithyroid Drugs† Beta-Adrenergic Blockers Cholelitholytic Agents Diabetes Agents, Oral Diuretics† Fungal Medications, Intravaginal, Systemic† Gastric Acidity and Peptic Ulcer Agents† Gastrointestinal Prokinetic Agents Ulcerative Colitis Agents Gout Treatment Agents Hemorrheologic Agents Hepatotoxic Drugs Hyperglycemic Agents Hypertensive Emergency Agents Hypnotics† Hypolipidemics† Bile Acid-Binding Resins† Fibric Acid Derivatives HMG-CoA Reductase Inhibitors† |
Leukotriene Receptor Antagonist Monoamine Oxidase Inhibitors Narcotics, prolonged Nonsteroidal Anti- Inflammatory Agents Proton Pump Inhibitors Psychostimulants Pyrazolones Salicylates Selective Serotonin Reuptake Inhibitors Steroids, Adrenocortical† Steroids, Anabolic (17-Alkyl Testosterone Derivatives) Thrombolytics Thyroid Drugs Tuberculosis Agents† Uricosuric Agents Vaccines Vitamins† |
|
| Specific Drugs Reported | |||
| also: other medications affecting blood elements which may modify hemostasis dietary deficiencies prolonged hot weather unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported. |
|||
| acetaminophen alcohol† allopurinol aminosalicylic acid amiodarone HCl argatroban aspirin atenolol atorvastatin† azithromycin bivalirudin capecitabine cefamandole cefazolin cefoperazone cefotetan cefoxitin ceftriaxone celecoxib cerivastatin chenodiol chloramphenicol chloral hydrate† chlorpropamide cholestyramine† cimetidine ciprofloxacin cisapride clarithromycin clofibrate cyclophosphamide† danazol dextran dextrothyroxine diazoxide |
diclofenac dicumarol diflunisal disulfiram doxycycline erythromycin esomeprazole ethacrynic acid ezetimibe fenofibrate fenoprofen fluconazole fluorouracil fluoxetine flutamide fluvastatin fluvoxamine gefitinib gemifibrozil glucagon halothane heparin ibuprofen ifosfamide indomethacin influenza virus vaccine itraconazole ketoprofen ketorolac lansoprazole lepirudin levamisole levofloxacin levothyroxine liothyronine |
lovastatin mefenamic acid methimazole† methyldopa methylphenidate methylsalicylate ointment (topical) metronidazole miconazole (intravaginal, oral, systemic) moricizine hydrochloride† nalidixic acid naproxen neomycin norfloxacin ofloxacin olsalazine omeprazole oxandrolone oxaprozin oxymetholone pantoprazole paroxetine penicillin G, intravenous pentoxifylline phenylbutazone phenytoin† piperacillin piroxicam pravastatin† prednisone† propafenone |
propoxyphene propranolol propylthiouracil† quinidine quinine rabeprazole ranitidine† rofecoxib sertraline simvastatin stanozolol streptokinase sulfamethizole sulfamethoxazole sulfinpyrazone sulfisoxazole sulindac tamoxifen tetracycline thyroid ticarcillin ticlopidine tissue plasminogen activator (t-PA) tolbutamide tramadol trimethoprim/ sulfamethoxazole urokinase valdecoxib valproate vitamin E warfarin overdose zafirlukast zileuton |
| edema hereditary coumarin resistance hyperlipemia |
hypothyroidism nephrotic syndrome |
| Classes of Drugs | ||
| Adrenal Cortical Steroid Inhibitors Antacids Antianxiety Agents Antiarrhythmics† Antibiotics† Anticonvulsants† Antidepressants† Antihistamines Antineoplastics† |
Antipsychotic Medications Antithyroid Drugs† Barbiturates Diuretics† Enteral Nutritional Supplements Fungal Medications, Systemic† Gastric Acidity and Peptic Ulcer Agents† Hypnotics† |
Hypolipidemics† Bile Acid-Binding Resins† HMG-CoA Reductase Inhibitors† Immunosuppressives Oral Contraceptives, Estrogen Containing Selective Estrogen Receptor Modulators Steroids, Adrenocortical† Tuberculosis Agents† Vitamins† |
| Specific Drugs Reported | |||
| also: diet high in vitamin K unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported. |
|||
| alcohol† aminoglutethimide amobarbital atorvastatin† azathioprine butabarbital butalbital carbamazepine chloral hydrate† chlordiazepoxide chlorthalidone |
cholestyramine† clozapine corticotropin cortisone cyclophosphamide† dicloxacillin ethchlorvynol glutethimide griseofulvin haloperidol meprobamate |
6-mercaptopurine methimazole† moricizine hydrochloride† nafcillin paraldehyde pentobarbital phenobarbital phenytoin† pravastatin† prednisone† primidone |
propylthiouracil† raloxifene ranitidine† rifampin secobarbital spironolactone sucralfate trazodone vitamin C (high dose) vitamin K warfarin underdosage |
| Coadministered Drug |
Dosing Schedule |
|
Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
|
Risperidone Dose Recommendation |
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Coadministered Drug |
Risperidone |
AUC |
Cm
a
x
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| Enzyme (CYP2D6) Inhibitors |
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| Fluoxetine |
20 mg/day |
2 or 3 mg twice daily |
1.4 |
1.5 |
Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine |
10 mg/day |
4 mg/day |
1.3 |
- |
Re-evaluate dosing. |
|
|
20 mg/day |
4 mg/day |
1.6 |
- |
Do not exceed 8 mg/day |
|
|
40 mg/day |
4 mg/day |
1.8 |
- |
|
| Enzyme (CYP3A/ PgP inducers) |
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| Carbamazepine |
573 ± 168 mg/day |
3 mg twice daily |
0.51 |
0.55 |
Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors |
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| Ranitidine |
150 mg twice daily |
1 mg single dose |
1.2 |
1.4 |
Dose adjustment not needed |
| Cimetidine |
400 mg twice daily |
1 mg single dose |
1.1 |
1.3 |
Dose adjustment not needed |
| Erythromycin |
500 mg four times daily |
1 mg single dose |
1.1 |
0.94 |
Dose adjustment not needed |
| Other Drugs |
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| Amitriptyline |
50 mg twice daily |
3 mg twice daily |
1.2 |
1.1 |
Dose adjustment not needed |
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| albuterol, | lomefloxacin |
| systemic and inhaled | mebendazole |
| amoxicillin | medroxyprogesterone |
| ampicillin, | methylprednisolone |
| with or without sulbactam | metronidazole |
| atenolol | metoprolol |
| azithromycin | nadolol |
| Caffeine, | nifedipine |
| dietary ingestion | nizatidine |
| cefactor | norfloxacin |
| co-trimoxazole | ofloxacin |
| (trimethoprim and | omeprazole |
| sulfamethoxazole) | prednisone, prednisolone |
| diltiazem | ranitidine |
| dirithromycin | rifabutin |
| enflurane | roxithromycin |
| famotidine | sorbitol |
| felodipine | (purgative doses do not |
| finasteride | inhibit theophylline |
| hydrocortisone | absorption) |
| isoflurane | sucralfate |
| isoniazid terbutaline, | systemic |
| isradipine | terfenadine |
| influenza vaccine | tetracycline |
| ketoconazole | tocainide |
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| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine, danazol | Do not exceed 10 mg simvastatin daily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Diltiazem | Do not exceed 40 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
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| Amiodarone Iodide (including iodine- containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
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| Cmax | AUC 0–24 hrs |
Cmax | AUC 0–24 hrs |
|
| Erythromycin (500 mg Q8h) |
+24% | +14% | +43% | +40% |
| Ketoconazole (200 mg Q12h) |
+45% | +39% | +43% | +72% |
| Azithromycin (500 mg day 1, 250 mg QD × 4 days) |
+15% | +5% | +15% | +4% |
| Fluoxetine (20 mg QD) |
+15% | +0% | +17% | +13% |
| Cimetidine (600 mg Q12h) |
+12% | +19% | -11% | -3% |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
|---|---|---|
| ↓= Decreased (induces lamotrigine glucuronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ? = Conflicting data. |
||
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine | Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide | ↓ lamotrigine | Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels. | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine | Increased lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. | |
| Coadministered Drugs | Effect on Rifabutin | Effect on Coadministered Drug | Comments |
|---|---|---|---|
| ANTIVIRALS | |||
| Amprenavir | 2.9-fold ↑ AUC, 2.2-fold ↑ Cmax | No significant change in kinetics. | A 50% reduction in the rifabutin dose is recommended when combined with amprenavir. Increased monitoring for adverse reactions is warranted. |
| Delavirdine | ND | Oral clearance ↑ 5-fold resulting in significantly lower mean trough plasma concentrations (18±15 to 1.0±0.7 µM) | Study conducted in HIV-1 infected patients Rifabutin is not recommended for patients dosed with delavirdine mesylate 400 mg q8h. |
| Didanosine | No significant change in kinetics. | No significant change in kinetics at steady state. | |
| Fosamprenavir/ritonavir | 64% ↑ AUC |
35% ↑ AUC and 36% ↑ Cmax, no effect Ctrough (amprenavir) | Dosage reduction of rifabutin by at least 75% (to 150 mg every other day or three times per week) is recommended when combined with fosamprenavir |
| Indinavir | 204% ↑ in AUC | 32%↓ in AUC | |
| Lopinavir/ritonavir | 5.7-fold ↑ AUC, 3.4 fold ↑ Cmax |
No significant change in lopinavir kinetics. | Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted. Further dosage reduction of rifabutin may be necessary. |
| Saquinavir | ND | 40% ↓ in AUC | |
| Ritonavir | 4 fold increase in AUC, 2.5 fold increase in Cmax | ND | In the presence of ritonavir the subsequent risk of side effects, including uveitis may be increased . If a protease inhibitor is required in a patient treated with rifabutin, agents other than ritonavir should be considered. |
| Tipranavir/ritonavir[133] | 2.9-fold ↑ AUC, 1.7-fold ↑ Cmax | No significant change in tipranavir kinetics. | Therapeutic drug monitoring of rifabutin is recommended. |
| Zidovudine | No significant change in kinetics. | Approximately 32%↓ in Cmax and AUC | A large controlled clinical study has shown that these changes are of no clinical relevance. |
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| ANTIFUNGALS | 82% ↑ in AUC | No significant change in steady-state plasma concentrations | |
| Itraconazole | ND | 70% to 75% ↓ in Cmax and AUC | One case report suggests a kinetic interaction resulting in an increase in serum rifabutin levels and a risk for developing uveitis in the presence of itraconazole. |
| Posaconazole | 31%↑ Cmax, 72%↑ AUC | 43%↓ Cmax, 49%↓ AUC | If the drugs are co-administered, patients should be monitored for adverse events associated with rifabutin administration. |
| Voriconazole | 195%↑ Cmax, 331%↑ AUC |
Rifabutin (300 mg once daily) decreased the Cmax and AUC of voriconazole at 200 mg twice daily by 69% and 78%, respectively. During co-administration with rifabutin, the Cmax and AUC of voriconazole at 350 mg twice daily were 96% and 68% of the levels when administered alone at 200 mg twice daily. At a voriconazole dose of 400 mg twice daily Cmax and AUC were 104% and 87% higher, respectively, compared with voriconazole alone at 200 mg twice daily. | If the benefit outweighs the risk, rifabutin may be coadministered with voriconazole if the maintenance dose of voriconazole is increased to 5 mg/kg intravenously every 12 hours or from 200 mg to 350 mg orally, every 12 hours (100 mg to 200 mg orally, every 12 hours in patients less than 40 kg). Careful monitoring of full blood counts and adverse events to rifabutin (e.g. uveitis) is recommended when rifabutin is coadministered with voriconazole |
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| Dapsone | ND | Approximately 27% to 40% ↓ in AUC | Study conducted in HIV infected patients (rapid and slow acetylators). |
| Sulfamethoxazole-Trimethoprim | No significant change in Cmax and AUC | Approximately 15% to 20% ↓ in AUC | In another study, only trimethoprim (not sulfamethoxazole) had 14% ↓ in AUC and 6%↓ in Cmax but were not considered clinically significant. |
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| Azithromycin | No PK interaction | No PK interaction | |
| Clarithromycin | Approximately 77% ↑ in AUC | Approximately 50%↓ in AUC | Study conducted in HIV infected patients. Dose of rifabutin should be adjusted in the presence of clarithromycin |
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| Ethambutol | ND | No significant change in AUC or Cmax | |
| Isoniazid | ND | Pharmacokinetics not affected | |
| Pyrazinamide | ND | ND | Study data being evaluated. |
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| Methadone | ND | No significant effect | No apparent effect of rifabutin on either peak levels of methadone or systemic exposure based upon AUC. Rifabutin kinetics not evaluated. |
| Ethinylestradiol | ND | 35%↓ AUC 20%↓ Cmax |
Patients should be advised to use other methods of contraception. |
| Norethindrone | ND | 46%↓ AUC | Patients should be advised to use other methods of contraception. |
| Tacrolimus | ND | ND | Authors report that rifabutin decreases tacrolimus trough blood levels. |
| Theophylline | ND | No significant change in AUC or Cmax compared with baseline. | |
| Concomitant Drug Class: Drug Name |
Effect on Concentration of Saquinavir or Concomitant Drug | Clinical Comment |
|---|---|---|
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|
Delavirdine |
↑ Saquinavir Effect on delavirdine is not well established |
Appropriate doses of the combination with respect to safety and efficacy have not been established. |
|
Efavirenz nevirapine |
↓ Saquinavir ↔ Efavirenz |
Appropriate doses of the combination of efavirenz or nevirapine and INVIRASE/ritonavir (1000/100 mg bid) with respect to safety and efficacy have not been established. |
|
Atazanavir |
↑ Saquinavir ↑ Ritonavir ↔ Atazanavir |
Appropriate dosing recommendations for this combination, with respect to efficacy and safety, have not been established. When 1600 mg INVIRASE/100 mg ritonavir and 300 mg atazanavir were coadministered, plasma concentrations of saquinavir and ritonavir were increased. |
|
Indinavir |
↑ Saquinavir Effect on indinavir is not well established |
Appropriate doses of the combination of indinavir and INVIRASE/ritonavir with respect to safety and efficacy have not been established. |
|
Lopinavir/ritonavir |
↔ Saquinavir ↔ Lopinavir ↓ Ritonavir |
Evidence from several clinical trials indicates that saquinavir concentrations achieved with the saquinavir and lopinavir/ritonavir combination are similar to those achieved following saquinavir/ritonavir 1000/100 mg. The recommended dose for this combination is saquinavir 1000 mg plus lopinavir/ritonavir 400/100 mg bid. |
|
Tipranavir/ritonavir |
↓ Saquinavir | Combining saquinavir with tipranavir/ritonavir is not recommended. |
|
Enfuvirtide |
Saquinavir soft gel capsules/ritonavir ↔ enfuvirtide |
No clinically significant interaction was noted from a study in 12 HIV patients who received enfuvirtide concomitantly with saquinavir soft gel capsules/ritonavir 1000/100 mg bid. No dose adjustments are required. |
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|
Lidocaine (systemic) |
↑ Antiarrhythmics | Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics given with INVIRASE/ritonavir. |
|
Warfarin |
↑ Warfarin | Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored. |
|
Carbamazepine |
↓ Saquinavir Effect on carbamazepine, phenobarbital, and phenytoin is not well established |
Use with caution, saquinavir may be less effective due to decreased saquinavir plasma concentrations in patients taking these agents concomitantly. |
|
Clarithromycin |
↑ Saquinavir ↑ Clarithromycin |
Appropriate doses of the combination of clarithromycin and INVIRASE/ritonavir with respect to safety and efficacy have not been established. Due to the known effect of ritonavir on clarithromycin concentrations, the following dose adjustments are recommended: For patients with renal impairment, the following dosage adjustments should be considered:
|
|
Ketoconazole |
↔ Saquinavir ↔ Ritonavir ↑ Ketoconazole |
Appropriate doses of the combination of ketoconazole or itraconazole and INVIRASE/ritonavir with respect to safety and efficacy have not been established. When INVIRASE/ritonavir and ketoconazole are coadministered, plasma concentration of ketoconazole was increased (see |
|
Rifabutin |
↓ Saquinavir ↑ Rifabutin |
Appropriate doses of the combination of rifabutin and INVIRASE/ritonavir with respect to safety and efficacy have not been established. |
|
Alprazolam, clorazepate, diazepam, flurazepam |
↑ Benzodiazepines | Clinical significance is unknown; however, a decrease in benzodiazepine dose may be needed. |
|
Intravenously administered Midazolam |
↑ Midazolam | Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, INVIRASE should not be given with orally administered midazolam [see |
|
Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine |
↑ Calcium channel blockers | Caution is warranted and clinical monitoring of patients is recommended. |
|
Dexamethasone |
↓ Saquinavir | Use with caution, saquinavir may be less effective due to decreased saquinavir plasma concentrations in patients taking these agents concomitantly. |
|
Digoxin |
↑ Digoxin Increases in serum digoxin concentration were greater in female subjects as compared to male subjects when digoxin was coadministered with INVIRASE/ritonavir. |
Concomitant use of INVIRASE/ritonavir with digoxin results in a significant increase in serum concentrations of digoxin. Caution should be exercised when INVIRASE/ritonavir and digoxin are coadministered; serum digoxin concentrations should be monitored and the dose of digoxin may need to be reduced when coadministered with INVIRASE/ritonavir (see |
|
Fluticasone |
↑ Fluticasone |
Concomitant use of fluticasone propionate and INVIRASE/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Coadministration of fluticasone propionate and INVIRASE/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects (see |
|
Atorvastatin, rosuvastatin |
↑ Atorvastatin ↑ Rosuvastatin |
Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as fluvastatin in combination with Invirase/ritonavir (see |
|
Cyclosporine, tacrolimus, rapamycin |
↑ Immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with INVIRASE/ritonavir. |
|
Methadone |
↓ Methadone | Dosage of methadone may need to be increased when coadministered with INVIRASE/ritonavir. |
|
Ethinyl estradiol |
↓ Ethinyl estradiol | Alternative or additional contraceptive measures should be used when estrogen-based oral contraceptives and INVIRASE/ritonavir are coadministered. |
|
Sildenafil |
↑ Sildenafil ↔ Saquinavir ↑ Vardenafil ↑ Tadalafil |
Use sildenafil with caution at reduced doses of 25 mg every 48 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir. Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir. Use tadalafil with caution at reduced doses of no more than 10 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir. |
|
Trazodone |
↑ Trazodone | Concomitant use of trazodone and INVIRASE/ritonavir may increase plasma concentration of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as INVIRASE/ritonavir, the combination should be used with caution and lower dose of trazodone should be considered. |
|
|
↑ Tricyclics | Therapeutic concentration monitoring is recommended for tricyclic antidepressants when coadministered with INVIRASE/ritonavir. |
|
|
↑ Saquinavir | When INVIRASE/ritonavir is co-administered with omeprazole, saquinavir concentrations are increased significantly. If omeprazole or another proton pump inhibitor is taken concomitantly with INVIRASE/ritonavir, caution is advised and monitoring for potential saquinavir toxicities is recommended, particularly gastrointestinal symptoms, increased triglycerides, and deep vein thrombosis. |
|
St. John's wort |
↓ Saquinavir | Coadministration may lead to loss of virologic response and possible resistance to INVIRASE or to the class of protease inhibitors (see |
| Garlic Capsules |
↓ Saquinavir | Coadministration of garlic capsules and saquinavir is not recommended due to the potential for garlic capsules to induce the metabolism of saquinavir which may result in sub-therapeutic saquinavir concentrations. |
|
|
Nevirapine or Concomitant Drug |
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| Atazanavir/Ritonavir | ↓ Atazanavir ↑ Nevirapine |
Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposureand there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures . | |
| Fosamprenavir* | ↓Amprenavir ↑Nevirapine |
Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. | |
| Fosamprenavir/Ritonavir* | ↓Amprenavir ↑Nevirapine | No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied. | |
| Indinavir* | ↓ Indinavir | The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established. | |
| Lopinavir/Ritonavir* | ↓Lopinavir | Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. | |
| Nelfinavir* | ↓Nelfinavir M8 Metabolite↓Nelfinavir Cmin | The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established. | |
| Saquinavir/ritonavir | The interaction between nevirapine and saquinavir/ritonavir has not been evaluated | The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established. |
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| Efavirenz* | ↓ Efavirenz | The appropriate doses of these combinations with respect to safety and efficacy have not been established. | |
| Delavirdine, Etravirine, Rilpivirine | Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial. | ||
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↓ Methadone | Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone- maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. | |
|
|
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. | |
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| Clarithromycin* | ↓ Clarithromycin↑ 14-OH clarithromycin | Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium aviumintracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered. | |
| Rifabutin* | ↑Rifabutin | Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. | |
| Rifampin* | ↓ Nevirapine | Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead. | |
|
|
Plasma concentrations of nevirapine and the anticonvulsant may be decreased. | Use with caution and monitor virologic response and levels of anticonvulsants. | |
|
|
↑Nevirapine | Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine- associated adverse events. | |
| Ketoconazole* | ↓ Ketoconazole | Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. | |
| Itraconazole | ↓ Itraconazole | Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug. | |
|
|
Plasma concentrations may be increased. | Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended. | |
|
|
Plasma concentrations may be decreased. | Appropriate doses for these combinations have not been established. | |
|
|
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. | |
|
|
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. | |
|
|
Plasma concentrations may be decreased. | Appropriate doses for these combinations have not been established. | |
|
|
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. | |
|
|
Plasma concentrations may be decreased. | Appropriate doses for this combination have not been established. | |
|
|
↓ Ethinyl estradiol ↓ Norethindrone | Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended. | |
| * The interaction between Nevirapine and the drug was evaluated in a clinical study. All other drug interactions shown are predicted. | |||
| Drug/Drug Class (Mechanism of Interaction by the Drug) |
Voriconazole Plasma Exposure (Cmax and AUCτ after 200 mg q12h) |
Recommendations for Voriconazole Dosage Adjustment/Comments |
|---|---|---|
| Rifampin (CYP450 Induction) |
Significantly Reduced |
|
| Efavirenz (CYP450 Induction) |
Significantly Reduced | When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h |
| High-dose Ritonavir (400 mg q12h) Low-dose Ritonavir (100 mg q12h) |
Significantly Reduced Reduced |
Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole |
| Carbamazepine (CYP450 Induction) |
Not Studied |
|
| Long Acting Barbiturates (CYP450 Induction) |
Not Studied |
|
| Phenytoin (CYP450 Induction) |
Significantly Reduced | Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg) |
| St. John's Wort (CYP450 inducer; P-gp inducer) |
Significantly Reduced |
|
| Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition) |
Increased | Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives |
| Fluconazole |
Significantly Increased | Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole. |
| Other HIV Protease Inhibitors (CYP3A4 Inhibition) |
|
No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors |
| Other NNRTIs (CYP3A4 Inhibition or CYP450 Induction) |
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to voriconazole Careful assessment of voriconazole effectiveness |
| Drug/Drug Class (Mechanism of Interaction by Voriconazole) |
Drug Plasma Exposure (Cmax and AUCτ) | Recommendations for Drug Dosage Adjustment/Comments |
|---|---|---|
| Sirolimus (CYP3A4 Inhibition) |
Significantly Increased |
|
| Rifabutin (CYP3A4 Inhibition) |
Significantly Increased |
|
| Efavirenz (CYP3A4 Inhibition) |
Significantly Increased | When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h |
| High-dose Ritonavir (400 mg q12h) Low-dose Ritonavir (100 mg q12h) |
No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ
Slight Decrease in Ritonavir Cmax and AUCτ |
Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole |
| Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition) |
Not Studied |
|
| Ergot Alkaloids (CYP450 Inhibition) |
Not Studied |
|
| Cyclosporine (CYP3A4 Inhibition) |
AUCτ Significantly Increased; No Significant Effect on Cmax | When initiating therapy with voriconazole in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary. |
| Methadone |
Increased | Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed |
| Fentanyl (CYP3A4 Inhibition) |
Increased | Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [ |
| Alfentanil (CYP3A4 Inhibition) | Significantly Increased | Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [ |
| Oxycodone (CYP3A4 Inhibition) | Significantly Increased | Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [ |
| NSAIDs (CYP2C9 Inhibition) |
Increased | Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [ |
| Tacrolimus (CYP3A4 Inhibition) |
Significantly Increased | When initiating therapy with voriconazole in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary. |
| Phenytoin (CYP2C9 Inhibition) |
Significantly Increased | Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin. |
| Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition) |
Increased | Monitoring for adverse events related to oral contraceptives is recommended during coadministration. |
| Warfarin (CYP2C9 Inhibition) |
Prothrombin Time Significantly Increased | Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed. |
| Omeprazole (CYP2C19/3A4 Inhibition) |
Significantly Increased | When initiating therapy with voriconazole in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors. |
| Other HIV Protease Inhibitors (CYP3A4 Inhibition) |
(Increased Plasma Exposure) |
No dosage adjustment for indinavir when coadministered with voriconazole Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors |
| Other NNRTIs (CYP3A4 Inhibition) |
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to NNRTI |
| Benzodiazepines (CYP3A4 Inhibition) |
(Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed. |
| HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition) |
(Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed. |
| Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition) |
(Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed. |
| Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition) |
Not Studied |
Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed. |
| Vinca Alkaloids (CYP3A4 Inhibition) |
Not Studied |
Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed. |
|
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|
|
|
Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
|
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|
Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
|
|
|
|
Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
|
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|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function. |
|
|
|
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|
|
Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
|
Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4 . Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
|
|
|
|
|
|
|
Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
|
|
|
|
Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
|
|
|
|
- Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
|
- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
|
- Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
|
- Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
|
- Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
|
- (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
|
Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
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||
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|
| Antrum | 10.48 ± 2.01 (n = 5) | 19.96 ± 4.71 (n = 5) |
| Fundus | 20.81 ± 7.64 (n = 5) | 24.25 ± 6.37 (n = 5) |
| Mucus | 4.15 ± 7.74 (n = 4) | 39.29 ± 32.79 (n = 4) |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine | Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide | ↓ lamotrigine | Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine | Increased lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
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|
| Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
|
|
|
| Amiodarone Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
|
|
|
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
|
|
|
|
|
|
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
| Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
|
|
|
|
|
|
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
|
|
|
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
|
|
|
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
| AED Coadministered | Dose of AED (mg/day) |
Oxcarbazepine Dose (mg/day) |
Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval) | Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval) |
| Carbamazepine | 400-2000 | 900 | nc |
40% decrease [CI:17% decrease, 57% decrease] |
| Phenobarbital | 100-150 | 600-1800 | 14% increase [CI: 2% increase, 24% increase] |
25% decrease [CI:12% decrease, 51% decrease] |
| Phenytoin | 250-500 | 600-1800 >1200-2400 |
nc up to 40% increase [CI: 12% increase, 60% increase] |
30% decrease [CI: 3% decrease, 48% decrease] |
| Valproic acid | 400-2800 | 600-1800 | nc |
18% decrease [CI:13% decrease, 40% decrease] |
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|
| a Should be administered at least 4 hours prior to WELCHOL | |
|
b No significant alteration of warfarin drug levels with warfarin and WELCHOL coadministration in an |
|
| c Cyclosporine levels should be monitored and, based on theoretical grounds, cyclosporine should be administered at least 4 hours prior to WELCHOL. | |
| Drugs with a known interaction with colesevelam | Cyclosporinec, glyburidea, levothyroxinea, and oral contraceptives containing ethinyl estradiol and norethindronea |
| Drugs with postmarketing reports consistent with potential drug-drug interactions when coadministered with WELCHOL | phenytoina, warfarinb |
| Drugs that do not interact with colesevelam based on |
cephalexin, ciprofloxacin, digoxin, warfarinb fenofibrate, lovastatin, metformin, metoprolol, pioglitazone, quinidine, repaglinide, valproic acid, verapamil |
| AED Coadministered | Dose of AED (mg/day) |
Oxcarbazepine Dose (mg/day) |
Influence of Oxcarbazepine on AED
Concentration (Mean Change, 90% Confidence Interval) |
Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval) |
|---|---|---|---|---|
|
|
||||
| Carbamazepine | 400-2000 | 900 | nc |
40% decrease [CI:17% decrease, 57% decrease] |
| Phenobarbital | 100-150 | 600-1800 | 14% increase [CI: 2% increase, 24% increase] |
25% decrease [CI:12% decrease, 51% decrease] |
| Phenytoin | 250-500 | 600-1800 less then 1200-2400 |
nc up to 40% increase [CI: 12% increase, 60% increase] |
30% decrease [CI: 3% decrease, 48% decrease] |
| Valproic acid | 400-2800 | 600-1800 | nc |
18% decrease [CI:13% decrease, 40% decrease] |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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|||
| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
| |
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|
||
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
||
|
|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
| |
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| |
|||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
|
|
|||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
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|
|||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
|
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|
|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
|
|
|
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
|
|
|
| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid grapefruit juice |
|
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|
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|
|
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|
|
|
| Amphetamines, cocaine, other sympathomimetic agents |
Additive hypertension, tachycardia, possibly cardiotoxicity |
| Atropine, scopolamine, antihistamines, other anticholinergic agents |
Additive or super-additive tachycardia, drowsiness |
| Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants |
Additive tachycardia, hypertension, drowsiness |
| Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants |
Additive drowsiness and CNS depression |
| Disulfiram | A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge |
| Fluoxetine | A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days |
| Antipyrine, barbiturates | Decreased clearance of these agents, presumably via competitive inhibition of metabolism |
| Theophylline | Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco |
| Opioids | Cross-tolerance and mutual potentiation |
| Naltrexone | Oral THC effects were enhanced by opioid receptor blockade. |
| Alcohol | Increase in the positive subjective mood effects of smoked marijuana |
|
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|
| Coadministered Drug | Dosing Schedule | Effect on Active Moiety(Risperidone + 9- Hydroxy- Risperidone (Ratio*) | Risperidone DoseRecommendation | ||
| Coadministered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6)Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 mg twice daily | 1.4 | 1.5 | Re-evaluate dosing. Donot exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | Re-evaluate dosing. Donot exceed 8 mg/day | |
| Enzyme (CYP3A/PgP inducers)Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards.Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A)Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
|
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|
|
| Dopamine / Dopamine Agonists
Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day). |
|
|
|
|
|
|
| Aminoglutethimide Amiodarone Iodide(including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
|
|
|
| Amiodarone Iodide(including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
|
|
|
| Antacids - Aluminum and Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
|
|
|
|
|
|
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic
Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
| Furosemide (> 80 mg
IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4, and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
|
|
|
|
|
|
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
|
|
|
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme
inhibitors decreases the peripheral conversion of T4 to
T3, leading to decreased T3
levels. However, serum T4 levels are usually normal but
may occasionally be slightly increased. In patients treated with large doses of
propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and
patients are clinically euthyroid. It should be noted that actions of particular
beta-adrenergic antagonists may be impaired when the hypothyroid patient is
converted to the euthyroid state. Short-term administration of large doses of
glucocorticoids may decrease serum T3 concentrations by
30% with minimal change in serum T4 levels. However,
long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG
production (see |
|
|
|
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine
Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral
Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms |
| Enzyme | Inhibitors | Inducers |
|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
| Drug Class | Specific Drugs |
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
| Interacting Agents | Prescribing Recommendations |
|---|---|
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
| Enzyme | Inhibitors | Inducers |
|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
| Drug Class | Specific Drugs |
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) | Do not exceed 40 mg atorvastatin daily |
| DRUG | DESCRIPTION OF INTERACTION |
| Sulfonylureas | Hypoglycemia potentiated. |
| Methotrexate | Decreases tubular reabsorption; clinical toxicity from methotrexate can result. |
| Oral Anticoagulants | Increased bleeding. |
| DRUG | DESCRIPTION OF INTERACTION |
| Corticosteroids | Decreases plasma salicylate level; tapering doses of steroids may promote salicylism. |
| Acidifying Agents | Increases plasma salicylate level. |
| Alkalizing Agents | Decreased plasma salicylate levels. |
| DRUG | DESCRIPTION OF INTERACTION |
| Heparin | Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients. |
| Pyrazinamide | Inhibits pyrazinamide-induced hyperuricemia. |
| Uricosuric Agents | Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited. |
| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
| Alpha-Blocker | Simultaneous dosing of Vardenafil 5 mg and Alpha-Blocker, Placebo-Subtracted |
Dosing of Vardenafil 5 mg and Alpha-Blocker Separated by 6 Hours, Placebo-Subtracted |
|
| Terazosin 5 or 10 mg daily |
Standing SBP | -3 (-6.7, 0.1) | -4 (-7.4, -0.5) |
| Supine SBP | -4 (-6.7, -0.5) | -4 (-7.1, -0.7) | |
| Tamsulosin 0.4 mg daily |
Standing SBP Supine SBP |
-6 (-9.9, -2.1) -4 (-7.0, -0.8) |
-4 (-8.3, -0.5) -5 (-7.9, -1.7) |
| Vardenafil 10 mg Placebo-subtracted |
Vardenafil 20 mg Placebo-subtracted |
|
| Standing SBP | -4 (-6.8, -0.3) | -4 (-6.8, -1.4) |
| Supine SBP | -5 (-8.2, -0.8) | -4 (-6.3, -1.8) |
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| Antacids, sucralfate, multivitamins, and other products containing multivalent cations | Moxifloxacin absorption is decreased. Administer AVELOX Tablet at least 4 hours before or 8 hours after these products. ( |
| Warfarin | Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. ( |
| Class IA and Class III antiarrhythmics: | Proarrhythmic effect may be enhanced. Avoid concomitant use. ( |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
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| Amiodarone Iodide (including iodine- containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
|
Drug Name |
Other Drugs |
|
| Thioridazine |
Increased plasma concentrations of thioridazine Potential QTc prolongation |
Concomitant use of thioridazine and BRISDELLE is contraindicated. |
| Pimozide |
Increased plasma concentrations of pimozide. Potential QTc prolongation |
Concomitant use of pimozide and BRISDELLE is contraindicated. |
| Tamoxifen |
Reduced plasma concentrations of active tamoxifen metabolite |
Consider avoiding concomitant use of tamoxifen and BRISDELLE. |
|
Tricyclic Antidepressant (TCA) (e.g., Desipramine) |
Increased plasma concentrations and elimination half-life |
Plasma TCA concentrations may need to be monitored and the dose of TCA may need to be reduced if a TCA is co-administered with BRISDELLE. Monitor tolerability. |
| Risperidone |
Increased plasma concentrations of risperidone |
A lower dosage of risperidone may be necessary (see the Full Prescribing Information for risperidone). Monitor tolerability. |
| Atomoxetine |
Increased exposure of atomoxetine |
A lower dosage of atomoxetine may be necessary (see Full Prescribing Information for atomoxetine). Monitor tolerability. |
| Drugs Highly Bound to Plasma Protein (e.g., Warfarin) |
Increased free plasma concentrations |
The dosage of warfarin may need to be reduced. Monitor tolerability and the International Normalized Ratio. |
| Digoxin |
Decreased plasma concentrations of digoxin |
Dosage of digoxin may need to be increased. Monitor digoxin concentrations and clinical effect. |
| Theophylline |
Increased plasma concentrations of theophylline |
Dosage of theophylline may need to be decreased. Monitor theophylline concentrations and tolerability. |
|
Drug Name |
on Paroxetine |
|
| Phenobarbital |
Decreased paroxetine exposure |
|
|
Phenytoin |
Decreased paroxetine exposure |
|
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Fosamprenavir/ Ritonavir |
Decreased plasma concentration of paroxetine |
No dose adjustment for BRISDELLE. Monitor clinical effect of BRISDELLE. |
| Cimetidine | Increased plasma concentration of paroxetine |
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|
Inflammatory Drugs |
Agents |
|
|
| ciprofloxacin |
melphalan | amphotericin B |
azapropazon |
cimetidine |
tacrolimus |
fibric acid derivatives (e.g., bezafibrate, fenofibrate) methotrexate |
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| diltiazem | fluconazole | azithromycin | methylprednisolone | allopurinol |
| nicardipine | itraconazole | clarithromycin | amiodarone | |
| verapamil | ketoconazole | erythromycin | bromocriptine | |
| quinupristin/ | colchicine | |||
| voriconazole | dalfopristin | danazol | ||
| imatinib | ||||
| metoclopramide | ||||
| nefazodone | ||||
| oral contraceptives |
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| nafcillin | carbamazepine | bosentan | St. John’s Wort |
| rifampin | oxcarbazepine | octreotide | |
| phenobarbital | orlistat | ||
| phenytoin | sulfinpyrazone | ||
| terbinafine | |||
| ticlopidine | |||
| Coadministered Drug | Dosing Schedule | Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio*) | Risperidone Dose Recommendation | ||
| Coadministered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6) Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 mg twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/ PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
| Concomitant Drug Class: Drug Name |
Effect on Concentration of Saquinavir or Concomitant Drug | Clinical Comment |
|---|---|---|
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|
Delavirdine |
↑ Saquinavir Effect on delavirdine is not well established |
Appropriate doses of the combination with respect to safety and efficacy have not been established. |
|
Efavirenz nevirapine |
↓ Saquinavir ↔ Efavirenz |
Appropriate doses of the combination of efavirenz or nevirapine and INVIRASE/ritonavir with respect to safety and efficacy have not been established. |
|
Atazanavir |
↑ Saquinavir ↑ Ritonavir ↔ Atazanavir |
Atazanavir in combination with INVIRASE/ritonavir should be used with caution. Additive effects on PR interval prolongation may occur with INVIRASE/ritonavir |
|
Indinavir |
↑ Saquinavir Effect on indinavir is not well established |
Appropriate doses of the combination of indinavir and INVIRASE/ritonavir with respect to safety and efficacy have not been established. |
|
Lopinavir/ritonavir |
↔ Saquinavir ↔ Lopinavir ↓ Ritonavir |
Evidence from several clinical trials indicates that saquinavir concentrations achieved with the saquinavir and lopinavir/ritonavir combination are similar to those achieved following saquinavir/ritonavir 1000/100 mg. The recommended dose for this combination is saquinavir 1000 mg plus lopinavir/ritonavir 400/100 mg bid. Lopinavir/ritonavir in combination with INVIRASE should be used with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE |
|
Tipranavir/ritonavir |
↓ Saquinavir |
Combining saquinavir with tipranavir/ritonavir is not recommended. |
|
Enfuvirtide |
Saquinavir soft gel capsules/ritonavir ↔ enfuvirtide |
No clinically significant interaction was noted from a study in 12 HIV-1 subjects who received enfuvirtide concomitantly with saquinavir soft gel capsules/ritonavir 1000/100 mg bid. No dose adjustments are required. |
|
Maraviroc |
↑ Maraviroc | Maraviroc dose should be 150 mg twice daily when coadministered with INVIRASE/ritonavir. For further details see complete prescribing information for Selzentry® (maraviroc). |
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||
| Ibutilide Sotalol |
Use with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE/ritonavir |
|
|
Warfarin |
↑ Warfarin | Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored. |
|
Carbamazepine |
↓ Saquinavir Effect on carbamazepine, phenobarbital, and phenytoin is not well established |
Use with caution. Saquinavir may be less effective due to decreased saquinavir plasma concentrations in patients taking these agents concomitantly. |
|
Colchicine |
↑ Colchicine |
0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Patients with renal or hepatic impairment should not be given colchicine with INVIRASE/ritonavir. |
|
Clarithromycin |
↑ Saquinavir ↑ Clarithromycin |
Due to the known effect of ritonavir on clarithromycin concentrations, the following dose adjustments are recommended for patients with renal impairment:
|
| Erythromycin Halofantrine Pentamidine |
Use with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE/ritonavir |
|
|
Ketoconazole itraconazole |
↔ Saquinavir ↔ Ritonavir ↑ Ketoconazole |
When INVIRASE/ritonavir and ketoconazole are coadministered, plasma concentrations of ketoconazole are increased (see |
|
Rifabutin |
↔ Saquinavir ↑ Rifabutin ↔ Ritonavir |
No dose adjustment of INVIRASE/ritonavir (1000/100 mg bid) is required if ritonavir-boosted INVIRASE is administered in combination with rifabutin. Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse events is warranted in patients receiving the combination. Consider monitoring rifabutin concentrations to ensure adequate exposure. |
|
Alprazolam, clorazepate, diazepam, flurazepam |
↑ Benzodiazepines | Clinical significance is unknown; however, a decrease in benzodiazepine dose may be needed. |
|
Intravenously administered Midazolam |
↑ Midazolam | Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, INVIRASE should not be given with orally administered midazolam |
|
Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine |
↑ Calcium channel blockers | Caution is warranted and clinical monitoring of patients is recommended. |
|
Dexamethasone |
↓ Saquinavir |
Use with caution. Saquinavir may be less effective due to decreased saquinavir plasma concentrations. |
|
|
↑ Digoxin Increases in serum digoxin concentration were greater in female subjects as compared to male subjects when digoxin was coadministered with INVIRASE/ritonavir. |
Concomitant use of INVIRASE/ritonavir with digoxin results in a significant increase in serum concentrations of digoxin. Caution should be exercised when INVIRASE/ritonavir and digoxin are coadministered; serum digoxin concentrations should be monitored and the dose of digoxin may need to be reduced when coadministered with INVIRASE/ritonavir. |
|
Bosentan |
↑ Bosentan |
In patients who have been receiving INVIRASE/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of INVIRASE/ritonavir. After at least 10 days following the initiation of INVIRASE/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. |
|
Salmeterol |
↑ Salmeterol | Concurrent administration of salmeterol with INVIRASE/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
|
Fluticasone |
↑ Fluticasone |
Concomitant use of fluticasone propionate and INVIRASE/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Coadministration of fluticasone propionate and INVIRASE/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. |
|
Atorvastatin |
↑ Atorvastatin |
Titrate atorvastatin dose carefully and use the lowest dose necessary; do not exceed atorvastatin 20 mg/day. |
|
Cyclosporine, tacrolimus, rapamycin |
↑ Immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with INVIRASE/ritonavir. |
|
Methadone |
↓ Methadone | Dosage of methadone may need to be increased when coadministered with INVIRASE/ritonavir. Use with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE/ritonavir |
|
Clozapine Haloperidol Mesoridazine Phenothiazines Thioridazine Ziprasidone |
Use with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE/ritonavir |
|
|
Ethinyl estradiol |
↓ Ethinyl estradiol | Alternative or additional contraceptive measures should be used when estrogen-based oral contraceptives and INVIRASE/ritonavir are coadministered. |
|
Sildenafil |
↑ Sildenafil ↔ Saquinavir ↑ Vardenafil ↑ Tadalafil Only the combination of sildenafil with saquinavir soft gelatin capsules has been studied at doses used for treatment of erectile dysfunction. |
May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism.
In patients receiving INVIRASE/ritonavir for at least one week, start Adcirca at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Avoid use of Adcirca during the initiation of INVIRASE/ritonavir. Stop Adcirca at least 24 hours prior to starting INVIRASE/ritonavir. After at least one week following the initiation of INVIRASE/ritonavir, resume Adcirca at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use sildenafil with caution at reduced doses of 25 mg every 48 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir. Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir. Use tadalafil with caution at reduced doses of no more than 10 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir. |
|
|
↑ Tricyclics | Therapeutic concentration monitoring is recommended for tricyclic antidepressants when coadministered with INVIRASE/ritonavir. |
|
|
↑ Saquinavir | When INVIRASE/ritonavir is co-administered with omeprazole, saquinavir concentrations are increased significantly. If omeprazole or another proton pump inhibitor is taken concomitantly with INVIRASE/ritonavir, caution is advised and monitoring for potential saquinavir toxicities is recommended, particularly gastrointestinal symptoms, increased triglycerides, deep vein thrombosis, and QT prolongation. |
|
St. John's wort |
↓ Saquinavir | Coadministration may lead to loss of virologic response and possible resistance to INVIRASE or to the class of protease inhibitors. |
| Garlic Capsules |
↓ Saquinavir | Coadministration of garlic capsules and saquinavir is not recommended due to the potential for garlic capsules to induce the metabolism of saquinavir which may result in sub-therapeutic saquinavir concentrations. |
|
|
|
|
|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
|
|
|
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
| *Not administered but an active metabolite of carbamazepine. | ||
| **No significant effect. | ||
| AED Coadministered |
AED Concentration |
Felbamate Concentration |
| Phenytoin | ↑ | ↓ |
| Valproate | ↑ | ↔** |
| Carbamazepine (CBZ) *CBZ epoxide |
↓ ↑ |
↓ |
| Phenobarbital | ↑ | ↓ |
|
|
|
|
|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
|
|
|
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
| albuterol, | lomefloxacin |
| systemic and inhaled | mebendazole |
| amoxicillin | medroxyprogesterone |
| ampicillin, | methylprednisolone |
| with or without sulbactam | metronidazole |
| atenolol | metoprolol |
| azithromycin | nadolol |
| caffeine, | nifedipine |
| dietary ingestion | nizatidine |
| cefactor | norfloxacin |
| co-trimoxazole | ofloxacin |
| (trimethoprim and | omeprazole |
| sulfamethoxazole) | prednisone, prednisolone |
| diltiazem | ranitidine |
| dirithromycin | rifabutin |
| enflurane | roxithromycin |
| famotidine | sorbitol |
| felodipine | (purgative doses do not |
| finasteride | inhibit theophylline |
| hydrocortisone | absorption) |
| isoflurane | sucralfate |
| isoniazid | terbutaline, systemic |
| isradipine | terfenadine |
| influenza vaccine | tetracycline |
| ketoconazole | tocainide |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
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| Amiodarone Iodide (including iodine- containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
|
|
(mg/day) |
Dose |
Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval) |
AED on MHD Concentration (Mean Change, 90% Confidence Interval) |
|
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|
57% decrease] |
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24% increase] |
51% decrease] |
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|
48% decrease] |
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60% increase] |
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|
40% decrease] |
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| Concomitant Drug Class: Drug Name |
Effect on Concentration of Raltegravir | Clinical Comment |
|---|---|---|
|
|
||
| atazanavir | ↑ | Atazanavir, a strong inhibitor of UGT1A1, increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended. |
| atazanavir/ritonavir | ↑ | Atazanavir/ritonavir increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended. |
| efavirenz | ↓ | Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed. |
| etravirine | ↓ | Etravirine reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed. |
| tipranavir/ritonavir | ↓ | Tipranavir/ritonavir reduces plasma concentrations of raltegravir. However, since comparable efficacy was observed for this combination relative to other ISENTRESS-containing regimens in Phase 3 studies 018 and 019, no dose adjustment is recommended. |
|
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| omeprazole | ↑ | Coadministration of medicinal products that increase gastric pH (e.g., omeprazole) may increase raltegravir levels based on increased raltegravir solubility at higher pH. However, since concomitant use of ISENTRESS with proton pump inhibitors and H2 blockers did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended. |
| rifampin | ↓ | Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of raltegravir. The recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin. |
| Interacting Agents | Prescribing Recommendations for LIPTRUZET |
|---|---|
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir), gemfibrozil | Avoid LIPTRUZET |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary. |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 10/20 mg LIPTRUZET daily. |
| HIV protease inhibitor (nelfinavir), hepatitis C protease inhibitor (boceprevir) | Do not exceed 10/40 mg LIPTRUZET daily. |
| Drug | Type of Interaction | Effect |
|---|---|---|
| Adenosine | Theophylline blocks adenosine receptors. | Higher doses of adenosine may be required to achieve desired effect. |
| Alcohol | A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours. | 30% increase |
| Allopurinol | Decreases theophylline clearance at allopurinol doses greater than or equal to 600 mg/day. | 25% increase |
| Aminoglutethimide | Increases theophylline clearance by induction of microsomal enzyme activity. | 25% decrease |
| Carbamazepine | Similar to aminoglutethimide. | 30% decrease |
| Cimetidine | Decreases theophylline clearance by inhibiting cytochrome P450 1A2. | 70% increase |
| Ciprofloxacin | Similar to cimetidine. | 40% increase |
| Clarithromycin | Similar to erythromycin. | 25% increase |
| Diazepam | Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. | Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression. |
| Disulfiram | Decreases theophylline clearance by inhibiting hydroxylation and demethylation. | 50% increase |
| Enoxacin | Similar to cimetidine. | 300% increase |
| Ephedrine | Synergistic CNS effects. | Increased frequency of nausea, nervousness, and insomnia. |
| Erythromycin | Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. | 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount. |
| Estrogen | Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. | 30% increase |
| Flurazepam | Similar to diazepam. | Similar to diazepam. |
| Fluvoxamine | Similar to cimetidine. | Similar to cimetidine. |
| Halothane | Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. | Increased risk of ventricular arrhythmias. |
| Interferon, human recombinant alpha-A | Decreases theophylline clearance. | 100% increase |
| Isoproterenol (IV) | Increases theophylline clearance. | 20% decrease |
| Ketamine | Pharmacologic | May lower theophylline seizure threshold. |
| Lithium | Theophylline increases renal lithium clearance. | Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%. |
| Lorazepam | Similar to diazepam. | Similar to diazepam. |
| Methotrexate (MTX) | Decreases theophylline clearance. | 20% increase after low dose MTX, higher dose MTX may have a greater effect. |
| Mexiletine | Similar to disulfiram. | 80% increase |
| Midazolam | Similar to diazepam. | Similar to diazepam. |
| Moricizine | Increases theophylline clearance. | 25% decrease |
| Pancuronium | Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. | Larger dose of pancuronium may be required to achieve neuromuscular blockade. |
| Pentoxifylline | Decreases theophylline clearance. | 30% increase |
| Phenobarbital (PB) | Similar to aminoglutethimide. | 25% decrease after two weeks of concurrent PB. |
| Phenytoin | Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. | Serum theophylline |
| Propafenone | Decreases theophylline clearance and pharmacologic interaction. | 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
| Propranolol | Similar to cimetidine and pharmacologic interaction. | 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline. |
| Rifampin | Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. | 20–40% decrease |
| Sulfinpyrazone | Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. | 20% decrease |
| Tacrine | Similar to cimetidine, also increases renal clearance theophylline. | 90% increase |
| Thiabendazole | Decreases theophylline clearance. | 190% increase |
| Ticlopidine | Decreases theophylline clearance. | 60% increase |
| Troleandomycin | Similar to erythromycin. | 33–100% increase depending on troleandomycin dose. |
| Verapamil | Similar to disulfiram. | 20% increase |
| albuterol, systemic and inhaled | medroxyprogesterone |
| amoxicillin | methylprednisolone |
| ampicillin, with or without sulbactam | metronidazole |
| atenolol | metoprolol |
| azithromycin | nadolol |
| caffeine, dietary ingestion | nifedipine |
| cefaclor | nizatidine |
| co-trimoxazole | norfloxacin |
| (trimethoprim and sulfamethoxazole) | ofloxacin |
| diltiazem | omeprazole |
| dirithromycin | prednisone, prednisolone |
| enflurane | ranitidine |
| famotidine | rifabutin |
| felodipine | roxithromycin |
| finasteride | sorbitol |
| hydrocortisone | (purgative doses do not inhibit |
| isoflurane | theophylline absorption) |
| isoniazid | sucralfate |
| isradipine | terbutaline, systemic |
| influenza vaccine | terfenadine |
| ketoconazole | tetracycline |
| lomefloxacin | tocainide |
| mebendazole |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
|---|---|---|
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine | Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide | ↓ lamotrigine | Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels. | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine | Increased lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
| blood dyscrasias - see cancer collagen vascular disease congestive heart failure |
diarrhea elevated temperature hepatic disorders infectious hepatitis jaundice |
hyperthyroidism poor nutritional state steatorrhea vitamin K deficiency |
| Classes of Drugs | |||
| 5-lipoxygenase Inhibitor Adrenergic Stimulants, Central Alcohol Abuse Reduction Preparations Analgesics Anesthetics, Inhalation Antiandrogen Antiarrhythmics† Antibiotics† Aminoglycosides (oral) Cephalosporins, parenteral Macrolides Miscellaneous Penicillins, intravenous, high dose Quinolones (fluoroquinolones) Sulfonamides, long acting Tetracyclines Anticoagulants Anticonvulsants† Antidepressants† Antimalarial Agents Antineoplastics† Antiparasitic/Antimicrobials |
Antiplatelet Drugs/Effects Antithyroid Drugs† Beta-Adrenergic Blockers Cholelitholytic Agents Diabetes Agents, Oral Diuretics† Fungal Medications, Intravaginal, Systemic† Gastric Acidity and Peptic Ulcer Agents† Gastrointestinal Prokinetic Agents Ulcerative Colitis Agents Gout Treatment Agents Hemorrheologic Agents Hepatotoxic Drugs Hyperglycemic Agents Hypertensive Emergency Agents Hypnotics† Hypolipidemics† Bile Acid-Binding Resins† Fibric Acid Derivatives HMG-CoA Reductase Inhibitors† |
Leukotriene Receptor Antagonist Monoamine Oxidase Inhibitors Narcotics, prolonged Nonsteroidal Anti- Inflammatory Agents Proton Pump Inhibitors Psychostimulants Pyrazolones Salicylates Selective Serotonin Reuptake Inhibitors Steroids, Adrenocortical† Steroids, Anabolic (17-Alkyl Testosterone Derivatives) Thrombolytics Thyroid Drugs Tuberculosis Agents† Uricosuric Agents Vaccines Vitamins† |
|
| Specific Drugs Reported | |||
| also: other medications affecting blood elements which may modify hemostasis dietary deficiencies prolonged hot weather unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported. |
|||
| acetaminophen alcohol† allopurinol aminosalicylic acid amiodarone HCl argatroban aspirin atenolol atorvastatin† azithromycin bivalirudin capecitabine cefamandole cefazolin cefoperazone cefotetan cefoxitin ceftriaxone celecoxib cerivastatin chenodiol chloramphenicol chloral hydrate† chlorpropamide cholestyramine† cimetidine ciprofloxacin cisapride clarithromycin clofibrate cyclophosphamide† danazol dextran dextrothyroxine diazoxide |
diclofenac dicumarol diflunisal disulfiram doxycycline erythromycin esomeprazole ethacrynic acid ezetimibe fenofibrate fenoprofen fluconazole fluorouracil fluoxetine flutamide fluvastatin fluvoxamine gefitinib gemifibrozil glucagon halothane heparin ibuprofen ifosfamide indomethacin influenza virus vaccine itraconazole ketoprofen ketorolac lansoprazole lepirudin levamisole levofloxacin levothyroxine liothyronine |
lovastatin mefenamic acid methimazole† methyldopa methylphenidate methylsalicylate ointment (topical) metronidazole miconazole (intravaginal, oral, systemic) moricizine hydrochloride† nalidixic acid naproxen neomycin norfloxacin ofloxacin olsalazine omeprazole oxandrolone oxaprozin oxymetholone pantoprazole paroxetine penicillin G, intravenous pentoxifylline phenylbutazone phenytoin† piperacillin piroxicam pravastatin† prednisone† propafenone |
propoxyphene propranolol propylthiouracil† quinidine quinine rabeprazole ranitidine† rofecoxib sertraline simvastatin stanozolol streptokinase sulfamethizole sulfamethoxazole sulfinpyrazone sulfisoxazole sulindac tamoxifen tetracycline thyroid ticarcillin ticlopidine tissue plasminogen activator (t-PA) tolbutamide tramadol trimethoprim/ sulfamethoxazole urokinase valdecoxib valproate vitamin E warfarin overdose zafirlukast zileuton |
| edema hereditary coumarin resistance hyperlipemia |
hypothyroidism nephrotic syndrome |
| Classes of Drugs | ||
| Adrenal Cortical Steroid Inhibitors Antacids Antianxiety Agents Antiarrhythmics† Antibiotics† Anticonvulsants† Antidepressants† Antihistamines Antineoplastics† |
Antipsychotic Medications Antithyroid Drugs† Barbiturates Diuretics† Enteral Nutritional Supplements Fungal Medications, Systemic† Gastric Acidity and Peptic Ulcer Agents† Hypnotics† |
Hypolipidemics† Bile Acid-Binding Resins† HMG-CoA Reductase Inhibitors† Immunosuppressives Oral Contraceptives, Estrogen Containing Selective Estrogen Receptor Modulators Steroids, Adrenocortical† Tuberculosis Agents† Vitamins† |
| Specific Drugs Reported | |||
| also: diet high in vitamin K unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported. |
|||
| alcohol† aminoglutethimide amobarbital atorvastatin† azathioprine butabarbital butalbital carbamazepine chloral hydrate† chlordiazepoxide chlorthalidone |
cholestyramine† clozapine corticotropin cortisone cyclophosphamide† dicloxacillin ethchlorvynol glutethimide griseofulvin haloperidol meprobamate |
6-mercaptopurine methimazole† moricizine hydrochloride† nafcillin paraldehyde pentobarbital phenobarbital phenytoin† pravastatin† prednisone† primidone |
propylthiouracil† raloxifene ranitidine† rifampin secobarbital spironolactone sucralfate trazodone vitamin C (high dose) vitamin K warfarin underdosage |
| Tissue | Clarithromycin | Clarithromycin + Omeprazole |
| Antrum | 10.48 ± 2.01 (n=5) | 19.96 ± 4.71 (n=5) |
| Fundus | 20.81 ± 7.64 (n=5) | 24.25 ± 6.37 (n=5) |
| Mucus | 4.15 ± 7.74 (n=4) | 39.29 ± 32.79 (n=4) |
| * Change relative to reference |
|||||
| Coadministered Drug |
Dosing Schedule |
Effect on Active Moiety (Risperidone + 9-Hydroxy- Risperidone Ratio*) |
Risperidone Dose Recommendation |
||
| Coadministered Drug |
Risperidone |
AUC |
Cmax
|
||
| Enzyme (CYP2D6) Inhibitors |
|
|
|
|
|
| Fluoxetine |
20 mg/day |
2 or 3 mg twice daily |
1.4 |
1.5 |
Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine |
10 mg/day |
4 mg/day |
1.3 |
- |
Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day |
4 mg/day |
1.6 |
- |
||
| 40 mg/day |
4 mg/day |
1.8 |
- |
||
| Enzyme (CYP3A/ PgP inducers) Inducers |
|||||
| Carbamazepine |
573 ± 168 mg/day |
3 mg twice daily |
0.51 |
0.55 |
Titrate dose upwards. Do not exceed twice the patients usual dose |
| Enzyme (CYP3A) Inhibitors |
|||||
| Ranitidine |
150 mg twice daily |
1 mg single dose |
1.2 |
1.4 |
Dose adjustment not needed |
| Cimetidine |
400 mg twice daily |
1 mg single dose |
1.1 |
1.3 |
Dose adjustment not needed |
| Erythromycin |
500 mg four times daily |
1 mg single dose |
1.1 |
0.94 |
Dose adjustment not needed |
| Other Drugs |
|||||
| Amitriptyline |
50 mg twice daily |
3 mg twice daily |
1.2 |
1.1 |
Dose adjustment not needed |
|
|
|
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|
|
| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
|
|
|
|
|
|
| Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
|
|
|
| Amiodarone Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
|
|
|
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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|
| Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
|
|
|
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
| % Change from Plavix (300 mg/75 mg) alone | ||||||
|---|---|---|---|---|---|---|
| Plavix plus | Cmax (ng/mL) | AUC | Platelet Inhibition |
|||
| Day 1 | Day 5 | Day 1 | Day 5 |
Day 1 | Day 5 | |
| Omeprazole |
↓46% | ↓42% | ↓45% | ↓40% | ↓39% | ↓21% |
| Pantoprazole 80 mg | ↓24% | ↓28% | ↓20% | ↓14% | ↓15% | ↓11% |
|
|
||
| Concomitant Drug |
Effect on Concentration of Lamotrigine or Concomitant Drug |
Clinical Comment |
| Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine ↓ levonorgestrel |
Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%. |
| Carbamazepine (CBZ) and CBZ epoxide |
↓ lamotrigine ? CBZ epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase CBZ epoxide levels |
| Phenobarbital/Primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40%. |
| Valproate |
↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
|
|
|
| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid grapefruit juice |
| Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) | VIAGRA 25 mg |
|---|---|
| Supine | 7.4 (-0.9, 15.7) |
| Standing | 6.0 (-0.8, 12.8) |
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| Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) | VIAGRA 100 mg |
|---|---|
| Supine | 7.9 (4.6, 11.1) |
| Standing |
4.3 (-1.8,10.3) |
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| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
|
|
or Concomitant Drug |
|
| Atazanavir/Ritonavir | ↓ Atazanavir ↑ Nevirapine |
Do not coadminister nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure. |
| Clarithromycin | ↓ Clarithromycin ↑ 14-OH clarithromycin |
Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against |
| Efavirenz | ↓ Efavirenz | There has been no determination of appropriate doses for the safe and effective use of this combination [ |
| Ethinyl estradiol and Norethindrone |
↓ Ethinyl estradiol ↓ Norethindrone |
Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended. |
| Fluconazole | ↑ Nevirapine | Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration and patients should be monitored closely for nevirapine-associated adverse events. |
| Fosamprenavir | ↓ Amprenavir ↑ Nevirapine |
Coadministration of nevirapine and fosamprenavir without ritonavir is not recommended. |
| Fosamprenavir/Ritonavir | ↓ Amprenavir ↑ Nevirapine |
No dosing adjustments are required when nevirapine is coadministered with 700 mg/100 mg of fosamprenavir/ritonavir twice daily. |
| Indinavir | ↓ Indinavir | Appropriate doses for this combination are not established, but an increase in the dosage of indinavir may be required. |
| Ketoconazole | ↓ Ketoconazole | Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. |
| Lopinavir/Ritonavir | ↓ Lopinavir |
A dose increase of lopinavir/ritonavir oral solution to 533 mg/133 mg twice daily with food is recommended in combination with nevirapine. In children 6 months to 12 years of age receiving lopinavir/ritonavir solution, consideration should be given to increasing the dose of lopinavir/ritonavir to 13/3.25 mg/kg for those 7 kg to < 15 kg; 11/2.75 mg/kg for those 15 kg to 45 kg; up to a maximum dose of 533 mg/133 mg twice daily. Refer to the lopinavir/ritonavir package insert for complete pediatric dosing instructions when lopinavir/ritonavir tablets are used in combination with nevirapine. |
| Methadone | ↓ Methadone | Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. |
| Nelfinavir | ↓ Nelfinavir M8 Metabolite ↓ Nelfinavir Cmin |
The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established. |
| Rifabutin | ↑ Rifabutin | Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. |
| Rifampin | ↓ Nevirapine | Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead. |
| Saquinavir/Ritonavir | The interaction between nevirapine and saquinavir/ritonavir has not been evaluated | The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established. |
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| Antiarrhythmics | Amiodarone, disopyramide, lidocaine | Plasma concentrations may be decreased. |
| Anticonvulsants | Carbamazepine, clonazepam, ethosuximide | Plasma concentrations may be decreased. |
| Antifungals | Itraconazole | Plasma concentrations of some azole antifungals may be decreased. Nevirapine and itraconazole should not be administered concomitantly due to a potential decrease in itraconazole plasma concentrations. |
| Calcium channel blockers | Diltiazem, nifedipine, verapamil | Plasma concentrations may be decreased. |
| Cancer chemotherapy | Cyclophosphamide | Plasma concentrations may be decreased. |
| Ergot alkaloids | Ergotamine | Plasma concentrations may be decreased. |
| Immunosuppressants | Cyclosporin, tacrolimus, sirolimus | Plasma concentrations may be decreased. |
| Motility agents | Cisapride | Plasma concentrations may be decreased. |
| Opiate agonists | Fentanyl | Plasma concentrations may be decreased. |
| Antithrombotics | Warfarin | Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended. |
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||
| AED Co-administered |
AED Concentration |
Topiramate Concentration |
| Phenytoin |
NC or 25% increasea
|
48% decrease |
| Carbamazepine (CBZ) |
NC |
40% decrease |
| CBZ epoxideb
|
NC |
NE |
| Valproic acid |
11% decrease |
14% decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NC at TPM doses up to 400 mg/day |
13% decrease |
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Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
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Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
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|
Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
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|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function. |
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|
Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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|
|
|
Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4 . Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
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|
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|
|
|
Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
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|
|
Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
|
|
|
|
- Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
|
- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
|
- Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
|
- Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
|
- Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
|
- (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
|
Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
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See |
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| Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz*, nevirapine* |
↓ lopinavir | KALETRA dose increase is recommended in all patients Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz. KALETRA should not be administered once daily in combination with efavirenz or nevirapine. |
| Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine |
↑ lopinavir | Appropriate doses of the combination with respect to safety and efficacy have not been established. |
| Nucleoside Reverse Transcriptase Inhibitor: didanosine |
KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food). |
|
| Nucleoside Reverse Transcriptase Inhibitor: tenofovir |
↑ tenofovir | KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir. |
| Nucleoside Reverse Transcriptase Inhibitor: abacavir zidovudine |
↓ abacavir ↓ zidovudine |
KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown. |
| HIV-1 Protease Inhibitor: amprenavir* |
↑ amprenavir ↓ lopinavir |
KALETRA should not be administered once daily in combination with amprenavir. |
| HIV-1 Protease Inhibitor: fosamprenavir/ritonavir |
↓ amprenavir ↓ lopinavir |
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor: indinavir* |
↑ indinavir | Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily |
| HIV-1 Protease Inhibitor: nelfinavir* |
↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir |
KALETRA should not be administered once daily in combination with nelfinavir. |
| HIV-1 Protease Inhibitor: ritonavir* |
↑ lopinavir | Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor: saquinavir* |
↑ saquinavir | The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir. |
| HIV-1 Protease Inhibitor: tipranavir |
↓ lopinavir AUC and Cmin | KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily). |
| HIV CCR5 – antagonist: maraviroc | ↑ maraviroc | Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry® (maraviroc). |
|
|
||
| Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), and quinidine |
↑ antiarrhythmics | Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA. |
| Anticancer Agents: vincristine vinblastine |
↑ anticancer agents | Concentrations of vincristine or vinblastine may be increased when co-administered with lopinavir/ritonavir (KALETRA) resulting in the potential for increased adverse events usually associated with these anticancer agents. Consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when lopinavir/ritonavir ( KALETRA) is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. |
| Anticoagulant: warfarin |
Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored. | |
| Anticonvulsants: carbamazepine, phenobarbital, phenytoin |
↓ lopinavir ↓ phenytoin |
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA. |
| Antidepressant: bupropion |
↓ bupropion ↓ active metabolite, hydroxybupropion |
Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion. |
| Antidepressant: trazodone |
↑ trazodone | Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered. |
| Anti-infective: clarithromycin |
↑ clarithromycin | For patients with renal impairment, the following dosage adjustments should be considered:
No dose adjustment for patients with normal renal function is necessary. |
| Antifungals: ketoconazole*, itraconazole, voriconazole |
↑ ketoconazole ↑ itraconazole ↓ voriconazole |
High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended. Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients. |
| Antimycobacterial: rifabutin* |
↑ rifabutin and rifabutin metabolite | Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary. |
| Antimycobacterial: rifampin |
↓ lopinavir | May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone. |
| Antiparasitic: atovaquone |
↓ atovaquone | Clinical significance is unknown; however, increase in atovaquone doses may be needed. |
| Benzodiazepines: parenterally administered midazolam | ↑ midazolam | Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam |
| Calcium Channel Blockers, dihydropyridine: e.g., felodipine, nifedipine, nicardipine |
↑ dihydropyridine calcium channel blockers | Caution is warranted and clinical monitoring of patients is recommended. |
| Corticosteroid: dexamethasone |
↓ lopinavir | Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly. |
| disulfiram/metronidazole | KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole). | |
| PDE5 inhibitors: sildenafil, tadalafil, vardenafil |
↑ sildenafil ↑ tadalafil ↑ vardenafil |
Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. It is recommended not to exceed the following doses:
|
| HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin |
↑ atorvastatin ↑ rosuvastatin |
Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with KALETRA. |
| Immunosuppressants: cyclosporine, tacrolimus, rapamycin |
↑ immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA. |
| Inhaled Steroid: fluticasone |
↑ fluticasone | Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect. |
| Narcotic Analgesic: methadone* |
↓ methadone | Dosage of methadone may need to be increased when co-administered with KALETRA. |
| Contraceptive: ethinyl estradiol* |
↓ ethinyl estradiol | Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended. |
|
|
|
|
|
|
| Carbamazepine | 400 to 2000 | 900 | nc |
40% decrease [CI: 17% decrease, 57% decrease] |
| Phenobarbital | 100 to 150 | 600 to 1800 | 14% increase [CI: 2% increase, 24% increase] | 25% decrease [CI: 12% decrease, 51% decrease] |
| Phenytoin | 250 to 500 | 600 to 1800 >1200 to 2400 | nc |
30% decrease [CI: 3% decrease, 48% decease] |
| Valproic acid | 400 to 2800 | 600 to 1800 | nc |
18% decrease [CI: 13% decrease, 40% decrease] |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine ↓ levonorgestrel |
Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%. |
| Carbamazepine (CBZ) and CBZ epoxide | ↓ lamotrigine ? CBZ epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase CBZ epoxide levels |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
|
|
|
|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
|
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|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone. |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
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| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine | Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide | ↓ lamotrigine | Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels. | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine | Increased lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. | |
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| ↑Indicates increase. ↓Indicates decrease. |
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| Drug | Effect | Clinical Comment |
| ganciclovir | ↑didanosine concentration | If there is no suitable alternative to ganciclovir, then use in combination with didanosine with caution. Monitor for didanosine-associated toxicity. |
| methadone | ↓didanosine concentration | If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is didanosine delayed-release capsules. Patients should be closely monitored for adequate clinical response when didanosine is coadministered with methadone, including monitoring for changes in HIV RNA viral load. Do not coadminister methadone with didanosine pediatric powder due to significant decreases in didanosine concentrations. |
| nelfinavir | No interaction 1 hour after didanosine | Administer nelfinavir 1 hour after didanosine. |
|
|
↑didanosine concentration |
|
| ↑ Indicates increase. | ||
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| Drugs that may cause pancreatic toxicity | ↑risk of pancreatitis | Use only with extreme caution. |
| Neurotoxic drugs | ↑risk of neuropathy | Use with caution. |
| *Range
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|
| Mean (SD) Pharmacokinetic Parameters in Healthy Young Subjects (n=15)
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|
Mean (± SD)
|
| Bioavailability
|
63% (34-108%)*
|
| Clearance (mL/min)
|
165 (55)
|
| Volume of Distribution (L)
|
76 (14)
|
| Half-Life (hours)
|
6.2 (2.1)
|
| *First-dose values; all other parameters are last-dose values
|
||
| Mean (SD) Noncompartmental Pharmacokinetic Parameters After Multiple Doses of 5 mg/day in Older Men
|
||
|
|
Mean (± SD)
|
|
| 45 to 60 years old (n=12)
|
≥70 years old (n=12)
|
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| AUC (ng•hr/mL)
|
389 (98)
|
463 (186)
|
| Peak Concentration (ng/mL)
|
46.2 (8.7)
|
48.4 (14.7)
|
| Time to Peak (hours)
|
1.8 (0.7)
|
1.8 (0.6)
|
| Half-Life (hours)*
|
6 (1.5)
|
8.2 (2.5)
|
| Coadministered Drug |
Dosing Schedule |
|
Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
|
Risperidone Dose Recommendation |
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|
Coadministered Drug |
Risperidone |
AUC |
Cm
a
x
|
|
| Enzyme (CYP2D6) Inhibitors |
|
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|
|
| Fluoxetine |
20 mg/day |
2 or 3 mg twice daily |
1.4 |
1.5 |
Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine |
10 mg/day |
4 mg/day |
1.3 |
- |
Re-evaluate dosing. |
|
|
20 mg/day |
4 mg/day |
1.6 |
- |
Do not exceed 8 mg/day |
|
|
40 mg/day |
4 mg/day |
1.8 |
- |
|
| Enzyme (CYP3A/ PgP inducers) |
|
|
|
|
|
| Carbamazepine |
573 ± 168 mg/day |
3 mg twice daily |
0.51 |
0.55 |
Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors |
|
|
|
|
|
| Ranitidine |
150 mg twice daily |
1 mg single dose |
1.2 |
1.4 |
Dose adjustment not needed |
| Cimetidine |
400 mg twice daily |
1 mg single dose |
1.1 |
1.3 |
Dose adjustment not needed |
| Erythromycin |
500 mg four times daily |
1 mg single dose |
1.1 |
0.94 |
Dose adjustment not needed |
| Other Drugs |
|
|
|
|
|
| Amitriptyline |
50 mg twice daily |
3 mg twice daily |
1.2 |
1.1 |
Dose adjustment not needed |
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|
| Carbamazepine | 400 to 2000 | 900 | nc1 | 40% decrease [CI: 17% decrease, 57% decrease] |
| Phenobarbital | 100 to 150 | 600 to 1800 | 14% increase [CI: 2% increase, 24% increase] | 25% decrease [CI: 12% decrease, 51% decrease] |
| Phenytoin | 250 to 500 | 600 to 1800 > 1200 to 2400 | nc 1,2 up to 40% increase3 [CI: 12% increase, 60% increase] | 30% decrease [CI: 3% decrease, 48% decrease] |
| Valproic acid | 400 to 2800 | 600 to 1800 | nc1 | 18% decrease [CI: 13% decrease, 40% decrease] |
| % Change from Plavix (300 mg/75 mg) alone | ||||||
| Plavix plus | Cmax (ng/mL) | AUC | Platelet Inhibition |
|||
| Day 1 | Day 5 | Day 1 | Day 5 |
Day 1 | Day 5 | |
| Omeprazole |
↓46% | ↓42% | ↓45% | ↓40% | ↓39% | ↓21% |
| Pantoprazole 80 mg | ↓24% | ↓28% | ↓20% | ↓14% | ↓15% | ↓11% |
|
|
|
| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine, danazol | Do not exceed 10 mg simvastatin daily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Diltiazem | Do not exceed 40 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
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|
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||
| atazanavir | ↑ | Atazanavir, a strong inhibitor of UGT1A1, increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended. |
| atazanavir/ritonavir | ↑ | Atazanavir/ritonavir increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended. |
| efavirenz | ↓ | Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed. |
| etravirine | ↓ | Etravirine reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed. |
| tipranavir/ritonavir | ↓ | Tipranavir/ritonavir reduces plasma concentrations of raltegravir. However, since comparable efficacy was observed for this combination relative to other ISENTRESS-containing regimens in Phase 3 studies 018 and 019, no dose adjustment is recommended. |
|
|
||
| omeprazole | ↑ | Coadministration of medicinal products that increase gastric pH (e.g., omeprazole) may increase raltegravir levels based on increased raltegravir solubility at higher pH. However, since concomitant use of ISENTRESS with proton pump inhibitors and H2 blockers did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended. |
| rifampin | ↓ | Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of raltegravir. The recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin. |
|
|
|
|
|
Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
|
|
Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) | Do not exceed 40 mg atorvastatin daily |
| Interacting Agents | Prescribing Recommendations |
| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone |
Avoid simvastatin |
| Gemfibrozil, cyclosporine, danazol |
Do not exceed 10 mg simvastatin daily |
| Amiodarone, verapamil |
Do not exceed 20 mg simvastatin daily |
| Diltiazem | Do not exceed 40 mg simvastatin daily |
| Grapefruit juice |
Avoid large quantities of grapefruit juice (>1 quart daily) |
| Coadministered Drug | Dosing Schedule | Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio |
Risperidone Dose Recommendation | ||
|---|---|---|---|---|---|
| Coadministered Drug | Risperidone | AUC | Cmax | ||
| Enzyme (CYP2D6) Inhibitors | |||||
| Fluoxetine | 20 mg/day | 2 or 3 mg twice daily | 1.4 | 1.5 | Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine | 10 mg/day | 4 mg/day | 1.3 | - | Re-evaluate dosing. Do not exceed 8 mg/day |
| 20 mg/day | 4 mg/day | 1.6 | - | ||
| 40 mg/day | 4 mg/day | 1.8 | - | ||
| Enzyme (CYP3A/ PgP inducers) Inducers | |||||
| Carbamazepine | 573 ± 168 mg/day | 3 mg twice daily | 0.51 | 0.55 | Titrate dose upwards. Do not exceed twice the patient's usual dose |
| Enzyme (CYP3A) Inhibitors | |||||
| Ranitidine | 150 mg twice daily | 1 mg single dose | 1.2 | 1.4 | Dose adjustment not needed |
| Cimetidine | 400 mg twice daily | 1 mg single dose | 1.1 | 1.3 | Dose adjustment not needed |
| Erythromycin | 500 mg four times daily | 1 mg single dose | 1.1 | 0.94 | Dose adjustment not needed |
| Other Drugs | |||||
| Amitriptyline | 50 mg twice daily | 3 mg twice daily | 1.2 | 1.1 | Dose adjustment not needed |
| DRUG | DESCRIPTION OF INTERACTION |
| Sulfonylureas | Hypoglycemia potentiated. |
| Methotrexate | Decreases tubular reabsorption; clinical toxicity from methotrexate can result. |
| Oral Anticoagulants | Increased bleeding. |
| DRUG | DESCRIPTION OF INTERACTION |
| Corticosteroids | Decreases plasma salicylate level; tapering doses of steroids may promote salicylism. |
| Acidifying Agents | Increases plasma salicylate level. |
| Alkalizing Agents | Decreased plasma salicylate levels. |
| DRUG | DESCRIPTION OF INTERACTION |
| Heparin | Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients. |
| Pyrazinamide | Inhibits pyrazinamide-induced hyperuricemia. |
| Uricosuric Agents | Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited. |
|
|
|
|
|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
|
|
|
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
|
|
|
| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid grapefruit juice |
| Interacting Drug | Interaction |
|---|---|
| Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents). | QUALAQUIN prolongs QT interval, ECG abnormalities including QT prolongation and Torsades des Pointes. Avoid concomitant use ( |
| Other antimalarials (e.g., halofantrine, mefloquine). | ECG abnormalities including QT prolongation. Avoid concomitant use ( |
| CYP3A4 inducers or inhibitors | Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine ( |
| CYP3A4 and CYP2D6 substrates | Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug ( |
| Digoxin | Increased digoxin plasma concentration ( |
|
|
|
| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine, danazol | Do not exceed 10 mg simvastatin daily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Diltiazem | Do not exceed 40 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
| Drug/Drug Class (Mechanism of Interaction by the Drug) |
Voriconazole Plasma Exposure (Cmax and AUCτ after 200 mg q12h) |
Recommendations for Voriconazole Dosage Adjustment/Comments |
|---|---|---|
| Rifampin (CYP450 Induction) |
Significantly Reduced |
|
| Efavirenz (CYP450 Induction) |
Significantly Reduced | When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h |
| High-dose Ritonavir (400 mg q12h) |
Significantly Reduced |
|
| Low-dose Ritonavir (100 mg q12h) |
Reduced | Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole |
| Carbamazepine (CYP450 Induction) |
Not Studied |
|
| Long Acting Barbiturates (CYP450 Induction) |
Not Studied |
|
| Phenytoin (CYP450 Induction) |
Significantly Reduced | Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg) |
| St. John's Wort (CYP450 inducer; P-gp inducer) |
Significantly Reduced |
|
| Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition) |
Increased | Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives |
| Fluconazole |
Significantly Increased | Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole. |
| Other HIV Protease Inhibitors (CYP3A4 Inhibition) |
|
No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors |
| Other NNRTIs (CYP3A4 Inhibition or CYP450 Induction) |
|
Frequent monitoring for adverse events and toxicity related to voriconazole |
| A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure) |
Careful assessment of voriconazole effectiveness |
| Drug/Drug Class (Mechanism of Interaction by Voriconazole) |
Drug Plasma Exposure (Cmax and AUCτ) |
Recommendations for Drug Dosage Adjustment/Comments |
|---|---|---|
| Sirolimus (CYP3A4 Inhibition) |
Significantly Increased |
|
| Rifabutin (CYP3A4 Inhibition) |
Significantly Increased |
|
| Efavirenz (CYP3A4 Inhibition) |
Significantly Increased | When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h |
| High-dose Ritonavir (400 mg q12h) |
No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ |
|
| Low-dose Ritonavir (100 mg q12h) |
Slight Decrease in Ritonavir Cmax and AUCτ | Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole |
| Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition) |
Not Studied |
|
| Ergot Alkaloids (CYP450 Inhibition) |
Not Studied |
|
| Cyclosporine (CYP3A4 Inhibition) |
AUCτ Significantly Increased; No Significant Effect on Cmax | When initiating therapy with VFEND in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary. |
| Methadone |
Increased | Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed |
| Fentanyl (CYP3A4 Inhibition) | Increased | Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary [ |
| Alfentanil (CYP3A4 Inhibition) | Significantly Increased | Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [ |
| Oxycodone (CYP3A4 Inhibition) | Significantly Increased | Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary [ |
| NSAIDs (CYP2C9 Inhibition) |
Increased | Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [ |
| Tacrolimus (CYP3A4 Inhibition) |
Significantly Increased | When initiating therapy with VFEND in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary. |
| Phenytoin (CYP2C9 Inhibition) |
Significantly Increased | Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin. |
| Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition) |
Increased | Monitoring for adverse events related to oral contraceptives is recommended during coadministration. |
| Warfarin (CYP2C9 Inhibition) |
Prothrombin Time Significantly Increased | Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed. |
| Omeprazole (CYP2C19/3A4 Inhibition) |
Significantly Increased | When initiating therapy with VFEND in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors. |
| Other HIV Protease Inhibitors (CYP3A4 Inhibition) |
|
No dosage adjustment for indinavir when coadministered with VFEND |
|
(Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors | |
| Other NNRTIs (CYP3A4 Inhibition) |
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to NNRTI |
| Benzodiazepines (CYP3A4 Inhibition) |
(Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed. |
| HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition) |
(Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed. |
| Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition) |
(Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed. |
| Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition) |
Not Studied |
Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed. |
| Vinca Alkaloids (CYP3A4 Inhibition) |
Not Studied |
Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed. |
| Drug | Description of Interaction |
|---|---|
| Tolbutamide; Sulfonylureas | Hypoglycemia potentiated |
| Methotrexate | Decrease tubular reabsorption; clinical toxicity from methotrexate can result |
| Oral Anticoagulants | Increased bleeding |
| Drug | Description |
|---|---|
| Corticosteroids | Decreases plasma salicylate level; tapering doses of steroids may promote salicylism |
| Ammonium Sulfate | Increases plasma salicylate level |
| Drug | Description |
|---|---|
| Heparin | Salicylate decreases platelet adhesivesness and interferes with hemostasis in heparin-treated patients |
| Pyrazinamide | Inhibits pyrazinamide-induced hyperuricemia |
| Uricosuric Agents | Effect of probenecid, sulfinpyrazone and phenylbutazone inhibited |
| AED Co-administered | AED Concentration | Topiramate Concentration |
|---|---|---|
| NC = Less than 10% change in plasma concentration. NE = Not Evaluated |
||
| Phenytoin | NC or 25% increase |
48% decrease |
| Carbamazepine (CBZ) | NC | 40% decrease |
| CBZ epoxide |
NC | NE |
| Valproic acid | 11% decrease | 14% decrease |
| Phenobarbital | NC | NE |
| Primidone | NC | NE |
| Lamotrigine | NC at TPM doses up to 400 mg/day | 13% decrease |
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e.g., |
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e.g., tri-iodothyronine |
2 weeks |
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2 weeks |
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corticosteroids, sulfonamides tolbutamide, perchlorate phenylbutazone lithium |
1 week 1 week 1-2 weeks 4 weeks |
|
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| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. ( |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents |
Carefully monitor blood glucose ( |
| Coadministered Drug |
Dosing Schedule |
Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*) |
Risperidone Dose Recommendation |
||
|
|
Coadministered Drug |
Risperidone |
AUC |
Cmax |
|
| Enzyme (CYP2D6) Inhibitors |
|
|
|
|
|
| Fluoxetine |
20 mg/day |
2 or 3 mg twice daily |
1.4 |
1.5 |
Re-evaluate dosing. Do not exceed 8 mg/day |
| Paroxetine |
10 mg/day |
4 mg/day |
1.3 |
|
Re-evaluate dosing. |
|
|
20 mg/day |
4 mg/day |
1.6 |
|
Do not exceed 8 mg/day |
|
|
40 mg/day |
4 mg/day |
1.8 |
|
|
| Enzyme (CYP3A/ PgP inducers) Inducers |
|
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|
|
|
| Carbamazepine |
573 ± 168 mg/day |
3 mg twice daily |
0.51 |
0.55 |
Titrate dose upwards. Do not exceed twice the patient’s usual dose |
| Enzyme (CYP3A) Inhibitors |
|
|
|
|
|
| Ranitidine |
150 mg twice daily |
1 mg single dose |
1.2 |
1.4 |
Dose adjustment not needed |
| Cimetidine |
400 mg twice daily |
1 mg single dose |
1.1 |
1.3 |
Dose adjustment not needed |
| Erythromycin |
500 mg four times daily |
1 mg single dose |
1.1 |
0.94 |
Dose adjustment not needed |
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| Other Drugs |
|
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| Amitriptyline |
50 mg twice daily |
3 mg twice daily |
1.2 |
1.1 |
Dose adjustment not needed |
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Hepatitis C protease inhibitor (boceprevir) |
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| Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol |
Contraindicated with simvastatin |
| Amiodarone, verapamil, diltiazem |
Do not exceed 10 mg simvastatin daily |
| Amlodipine, ranolazine |
Do not exceed 20 mg simvastatin daily |
| Grapefruit juice |
Avoid large quantities of grapefruit juice (>1 quart daily) |
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| AED Co-administered | AED Concentration | Topiramate Concentration |
|---|---|---|
| NC = Less than 10% change in plasma concentration. | ||
| NE = Not Evaluated | ||
| Phenytoin | NC or 25% increase |
48% decrease |
| Carbamazepine (CBZ) | NC | 40% decrease |
| CBZ epoxide |
NC | NE |
| Valproic acid | 11% decrease | 14% decrease |
| Phenobarbital | NC | NE |
| Primidone | NC | NE |
| Lamotrigine | NC at TPM doses up to 400 mg/day | 13% decrease |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
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| Amiodarone Iodide (including iodine- containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
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Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
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Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
|
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|
|
|
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
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|
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
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Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
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Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
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Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
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Thereapy wih interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
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Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
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| Increased Risk of Myopathy/Rhabdomyolysis ( |
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| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| Lopinavir plus ritonavir | Use lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) |
Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) | Do not exceed 40 mg atorvastatin daily |
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| HIV-1 Protease Inhibitor: fosamprenavir/ritonavir |
↓ amprenavir ↓ lopinavir |
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor: indinavir* |
↑ indinavir | Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily |
| HIV-1 Protease Inhibitor: nelfinavir* |
↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir |
KALETRA should not be administered once daily in combination with nelfinavir |
| HIV-1 Protease Inhibitor: ritonavir* |
↑ lopinavir | Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor: saquinavir* |
↑ saquinavir | The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir. |
| HIV-1 Protease Inhibitor: tipranavir |
↓ lopinavir AUC and Cmin | KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily). |
| HIV CCR5 – Antagonist: maraviroc |
↑ maraviroc | Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry® (maraviroc). |
| Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz*, nevirapine* |
↓ lopinavir | KALETRA dose increase is recommended in all patients Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz. KALETRA should not be administered once daily in combination with efavirenz or nevirapine |
| Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine |
↑ lopinavir | Appropriate doses of the combination with respect to safety and efficacy have not been established. |
| Nucleoside Reverse Transcriptase Inhibitor: didanosine |
KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food). |
|
| Nucleoside Reverse Transcriptase Inhibitor: tenofovir |
↑ tenofovir | KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir. |
| Nucleoside Reverse Transcriptase Inhibitors: abacavir zidovudine |
↓ abacavir ↓ zidovudine |
KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown. |
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| Antiarrhythmics e.g.: amiodarone, bepridil, lidocaine (systemic), quinidine |
↑ antiarrhythmics | Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA. |
| Anticancer Agents: vincristine, vinblastine, dasatinib, nilotinib |
↑ anticancer agents | Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents. For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions. |
| Anticoagulants: warfarin, rivaroxaban |
↑ rivaroxaban | Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored. Avoid concomitant use of rivaroxaban and KALETRA. Co-administration of KALETRA and rivaroxaban is expected to result in increased exposure of rivaroxaban which may lead to risk of increased bleeding. |
| Anticonvulsants: carbamazepine, phenobarbital, phenytoin |
↓ lopinavir ↓ phenytoin |
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA. |
| Anticonvulsants: lamotrigine, valproate |
↓ lamotrigine ↓ or ↔ valproate |
Co-administration of KALETRA and lamotrigine or valproate may decrease the exposure of lamotrigine or valproate. A dose increase of lamotrigine or valproate may be needed when co-administered with KALETRA and therapeutic concentration monitoring for lamotrigine may be indicated; particularly during dosage adjustments |
| Antidepressant: bupropion |
↓ bupropion ↓ active metabolite, hydroxybupropion |
Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion. |
| Antidepressant: trazodone |
↑ trazodone | Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered. |
| Anti-infective: clarithromycin |
↑ clarithromycin | For patients with renal impairment, the following dosage adjustments should be considered: • For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. • For patients with CLCR < 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary. |
| Antifungals: ketoconazole*, itraconazole, voriconazole |
↑ ketoconazole ↑ itraconazole ↓ voriconazole |
High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended. Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients. |
| Anti-gout: colchicine |
↑ colchicine | Patients with renal or hepatic impairment should not be given colchicine with KALETRA. 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). |
| Antimycobacterial: rifabutin* |
↑ rifabutin and rifabutin metabolite | Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary. |
| Antimycobacterial: rifampin |
↓ lopinavir | May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone |
| Antiparasitic: atovaquone |
↓ atovaquone | Clinical significance is unknown; however, increase in atovaquone doses may be needed. |
| Benzodiazepines: parenterally administered midazolam | ↑ midazolam | Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam |
| Contraceptive: ethinyl estradiol* |
↓ ethinyl estradiol | Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended. |
| Corticosteroids (systemic): e.g. budesonide, dexamethasone, prednisone |
↓ lopinavir ↑ glucocorticoids |
Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly. Concomitant use may result in increased steroid concentrations and reduced serum cortisol concentrations. Concomitant use of glucocorticoids that are metabolized by CYP3A, particularly for long-term use, should consider the potential benefit of treatment versus the risk of systemic corticosteroid effects. Concomitant use may increase the risk for development of systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression. |
| Dihydropyridine Calcium Channel Blockers: e.g. felodipine, nifedipine, nicardipine |
↑ dihydropyridine calcium channel blockers | Caution is warranted and clinical monitoring of patients is recommended. |
| Disulfiram/metronidazole | KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole). | |
| Endothelin Receptor Antagonists: bosentan |
↑ bosentan |
In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. |
| HCV-Protease Inhibitor: boceprevir |
↓ lopinavir ↓ boceprevir ↓ ritonavir |
It is not recommended to co-administer KALETRA and boceprevir. Concomitant administration of KALETRA and boceprevir reduced boceprevir, lopinavir and ritonavir steady-state exposures |
| HCV-Protease Inhibitor: telaprevir |
↓ telaprevir ↔ lopinavir |
It is not recommended to co-administer KALETRA and telaprevir. Concomitant administration of KALETRA and telaprevir reduced steady-state telaprevir exposure, while the steady-state lopinavir exposure was not affected |
| HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin |
↑ atorvastatin ↑ rosuvastatin |
Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day. See Drugs with No Observed or Predicted Interactions with KALETRA |
| Immunosuppressants: e.g. cyclosporine, tacrolimus, sirolimus |
↑ immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA. |
| Inhaled or Intranasal Steroids e.g.: fluticasone, budesonide |
↑ glucocorticoids | Concomitant use of KALETRA and fluticasone or other glucocorticoids that are metabolized by CYP3A is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. Concomitant use may result in increased steroid concentrations and reduce serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during postmarketing use in patients when certain ritonavir-containing products have been co-administered with fluticasone propionate or budesonide. |
| Long-acting beta-adrenoceptor Agonist: salmeterol |
↑ salmeterol | Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
| Narcotic Analgesics: methadone,* fentanyl |
↓ methadone ↑ fentanyl |
Dosage of methadone may need to be increased when co-administered with KALETRA. Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA. |
| PDE5 inhibitors: avanafil, sildenafil, tadalafil, vardenafil |
↑ avanafil ↑ sildenafil ↑ tadalafil ↑ vardenafil |
Do not use KALETRA with avanafil because a safe and effective avanafil dosage regimen has not been established. Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA The following dose adjustments are recommended for use of tadalafil (Adcirca®) with KALETRA: In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: It is recommended not to exceed the following doses: • Sildenafil: 25 mg every 48 hours • Tadalafil: 10 mg every 72 hours • Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events. |
| * |
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| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. ( |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents |
Carefully monitor blood glucose ( |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
|
Decreased Lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide |
|
Addition of carbamazepine decreases Lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels. | |
| Phenobarbital/Primidone | ↓ Lamotrigine | Decreased Lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ Lamotrigine | Decreased Lamotrigine concentration approximately 40%. |
| Rifampin | ↓ Lamotrigine | Decreased Lamotrigine AUC approximately 40%. |
| Valproate |
|
Increased Lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
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| Antiarrhythmics | digoxin, dofetilide |
| Anticonvulsants | carbamazepine |
| Antimycobacterials | rifabutin |
| Antineoplastics | busulfan, docetaxel, vinca alkaloids |
| Antipsychotics | pimozide |
| Benzodiazepines | alprazolam, diazepam, midazolam, |
| Calcium Channel Blockers | dihydropyridines, (including felodipine |
| Gastrointestinal Motility Agents | cisapride |
| HMG CoA-Reductase Inhibitors | atorvastatin, cerivastatin, lovastatin, |
| Immunosuppressants | cyclosporine, tacrolimus, sirolimus |
| Oral Hypoglycemics | oral hypoglycemics |
| Protease Inhibitors | indinavir, ritonavir, saquinavir |
| Other | methadone |
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| Anticonvulsants | carbamazepine, phenobarbital, phenytoin |
| Antimycobacterials | isoniazid, rifabutin, rifampin |
| Gastric Acid Suppressors/Neutralizers | antacids, H2-receptor antagonists, proton pump inhibitors |
| Non-nucleoside Reverse Transcriptase Inhibitors | nevirapine |
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| Macrolide Antibiotics | clarithromycin, erythromycin |
| Protease Inhibitors | indinavir, ritonavir |
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) | Do not exceed 40 mg atorvastatin daily |
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| Concomitant Drug |
Effect on Concentration of Lamotrigine or Concomitant Drug |
Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine ↓ levonorgestrel |
Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%. |
| Carbamazepine and carbamazepine epoxide |
↓ lamotrigine ? carbamazepine epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels. |
| Phenobarbital/Primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40%. |
| Valproate |
↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
| Oral hypoglycemics | Coumarin-type anticoagulants | Phenytoin |
| Cyclosporine | Rifampin | Theophylline |
| Terfenadine | Cisapride | Astemizole |
| Rifabutin | Voriconazole | Tacrolimus |
| Short-acting benzodiazepines | Triazolam | Oral contraceptives |
| Pimozide | Hydrochlorothiazide | Alfentanil |
| Amitriptyline, nortriptyline | Amphotericin B | Azithromycin |
| Carbamazepine | Calcium channel blockers | Celecoxib |
| Cyclophosphamide | Fentanyl | Halofantrine |
| HMG-CoA reductase inhibitors | Losartan | Methadone |
| Non-steroidal anti-inflammatory drugs | Prednisone | Saquinavir |
| Sirolimus | Vinca alkaloids | Vitamin A |
| Zidovudine |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
|
Decreased Lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide |
|
Addition of carbamazepine decreases Lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels. | |
| Phenobarbital/Primidone | ↓ Lamotrigine | Decreased Lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ Lamotrigine | Decreased Lamotrigine concentration approximately 40%. |
| Rifampin | ↓ Lamotrigine | Decreased Lamotrigine AUC approximately 40%. |
| Valproate |
|
Increased Lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
| Drug | Effect | Clinical Comment |
|---|---|---|
| ↑ Indicates increase. | ||
| ↓ Indicates decrease. | ||
| a The dosing recommendation for coadministration of VIDEX EC and tenofovir disoproxil fumarate with respect to meal consumption differs from that of VIDEX. See the complete prescribing information for VIDEX EC. | ||
| ciprofloxacin | ↓ ciprofloxacin concentration | Administer VIDEX at least 2 hours after or 6 hours before ciprofloxacin. |
| delavirdine | ↓ delavirdine concentration | Administer VIDEX 1 hour after delavirdine. |
| ganciclovir | ↑ didanosine concentration | If there is no suitable alternative to ganciclovir, then use in combination with VIDEX with caution. Monitor for didanosine-associated toxicity. |
| indinavir | ↓ indinavir concentration | Administer VIDEX 1 hour after indinavir. |
| methadone | ↓ didanosine concentration | Do not coadminister methadone with VIDEX pediatric powder due to significant decreases in didanosine concentrations. If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is VIDEX EC. Patients should be closely monitored for adequate clinical response when VIDEX EC is coadministered with methadone, including monitoring for changes in HIV RNA viral load. |
| nelfinavir | No interaction 1 hour after didanosine | Administer nelfinavir 1 hour after VIDEX. |
| tenofovir disoproxil fumarate | ↑ didanosine concentration | A dose reduction of VIDEX to the following dosage once daily is recommended.a
|
| Drug or Drug Class | Effect | Clinical Comment |
|---|---|---|
| ↑ Indicates increase. | ||
| ↓ Indicates decrease. | ||
|
a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of VIDEX is recommended [ |
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b [ |
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| Drugs that may cause pancreatic toxicity | ↑ risk of pancreatitis | Use only with extreme cautiona |
| Neurotoxic drugs | ↑ risk of neuropathy | Use with cautionb |
| Antacids containing magnesium or aluminum | ↑ side effects associated with antacid components | Use caution with VIDEX Pediatric Powder for Oral Solution |
| Azole antifungals | ↓ ketoconazole or itraconazole concentration | Administer drugs such as ketoconazole or itraconazole at least 2 hours before VIDEX. |
| Quinolone antibiotics (see also ciprofloxacin in |
↓ quinolone concentration | Consult package insert of the quinolone. |
| Tetracycline antibiotics | ↓ antibiotic concentration | Consult package insert of the tetracycline. |
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| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
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| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
| Concomitant Drug Class: Drug Name | Effect on Concentration |
Clinical Comment |
|---|---|---|
|
antacids (e.g., aluminium, magnesium hydroxide, or calcium carbonate) |
↔ rilpivirine (antacids taken at least 2 hours before or at least 4 hours after rilpivirine) ↓ rilpivirine (concomitant intake) |
The combination of COMPLERA and antacids should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). Antacids should only be administered either at least 2 hours before or at least 4 hours after COMPLERA. |
|
fluconazole itraconazole ketoconazole posaconazole voriconazole |
↑ rilpivirine ↓ ketoconazole |
Concomitant use of COMPLERA with azole antifungal agents may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when COMPLERA is coadministered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are coadministered with COMPLERA. |
|
cimetidine famotidine nizatidine ranitidine |
↔ rilpivirine (famotidine taken 12 hours before rilpivirine or 4 hours after rilpivirine) ↓ rilpivirine (famotidine taken 2 hours before rilpivirine) |
The combination of COMPLERA and H2-receptor antagonists should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). H2-receptor antagonists should only be administered at least 12 hours before or at least 4 hours after COMPLERA. |
|
clarithromycin erythromycin telithromycin |
↑ rilpivirine ↔ clarithromycin ↔ erythromycin ↔ telithromycin |
Concomitant use of COMPLERA with clarithromycin, erythromycin or telithromycin may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Where possible, alternatives such as azithromycin should be considered. |
|
methadone |
↓ R(–) methadone ↓ S(+) methadone ↔ rilpivirine ↔ methadone |
No dose adjustments are required when initiating coadministration of methadone with COMPLERA. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients. |
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|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
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|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
| albuterol, | famotidine | nizatidine |
| systemic and inhaled | felodipine | norfloxacin |
| amoxicillin | finasteride | ofloxacin |
| ampicillin, | hydrocortisone | omeprazole |
| with or without | isoflurane | prednisone, prednisolone |
| sulbactam | isoniazid | ranitidine |
| atenolol | isradipine | rifabutin |
| azithromycin | influenza vaccine | roxithromycin |
| caffeine, | ketoconazole | sorbitol |
| dietary ingestion | lomefloxacin | (purgative doses do not |
| cefaclor | mebendazole | inhibit theophylline |
| co-trimoxazole | medroxyprogesterone | absorption) |
| (trimethoprim and | methylprednisolone | sucralfate |
| sulfamethoxazole) | metronidazole | terbutaline, systemic |
| diltiazem | metoprolol | terfenadine |
| dirithromycin | nadolol | tetracycline |
| enflurane | nifedipine | tocainide |
| NA – Not available/reported | |||
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|||
| Digoxin Serum Concentration Increase |
Digoxin AUC Increase |
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|
| Amiodarone | 70% | NA | Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30% to 50% or by modifying the dosing frequency and continue monitoring. |
| Captopril | 58% | 39% | |
| Clarithromycin | NA | 70% | |
| Dronedarone | NA | 150% | |
| Gentamicin | 129-212% | NA | |
| Erythromycin | 100% | NA | |
| Itraconazole | 80% | NA | |
| Nitrendipine | 57% | 15% | |
| Propafenone | NA | 60-270% | |
| Quinidine | 100% | NA | |
| Ranolazine | 50% | NA | |
| Ritonavir | NA | 86% | |
| Tetracycline | 100% | NA | |
| Verapamil | 50-75% | NA | |
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| Atorvastatin | 22% | 15% | Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15% to 30% or by modifying the dosing frequency and continue monitoring. |
| Carvedilol | 16% | 14% | |
| Diltiazem | 20% | NA | |
| Indomethacin | 40% | NA | |
| Nefazodone | 27% | 15% | |
| Nifedipine | 45% | NA | |
| Propantheline | 24% | 24% | |
| Quinine | NA | 33% | |
| Saquinavir | 27% | 49% | |
| Spironolactone | 25% | NA | |
| Telmisartan | 20-49% | NA | |
| Tolvaptan | 30% | NA | |
| Trimethoprim | 22-28% | NA | |
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| Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole, quinine, rabeprazole, |
Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary. | ||
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| Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate, sulfasalazine |
Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20 % to 40 % as necessary. | ||
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|||
| Please refer to section 12 for a complete list of drugs which were studies but reported no significant changes on digoxin exposure. |
No additional actions are required. | ||
| Drugs that Affect Renal Function | Caution should be exercised when combining digoxin with any drug that may cause significant deterioration in renal function (e.g., ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDs], COX-2 inhibitors) since a decline in glomerular filtration or tubular secretion may impair the excretion of digoxin. | |
| Antiarrthymics | Dofetilide | Concomitant administration with digoxin was associated with a higher rate of torsades de pointes |
| Sotalol | Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin. | |
| Dronedarone | Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin. | |
| Parathyroid Hormone Analog | Teriparatide | Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium. |
| Thyroid supplement | Thyroid | Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin. |
| Sympathomimetics | Epinephrine Norepinephrine Dopamine |
Can increase the risk of cardiac arrhythmias |
| Neuromuscular Blocking Agents | Succinylcholine | May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin. |
| Supplements | Calcium | If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients. |
| Beta-adrenergic blockers and calcium channel blockers | Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block. | |
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| Drug | Effect | |
|---|---|---|
| Phenylephrine with prior administration of monoamine oxidase inhibitors (MAOI). |
Cardiac pressor response potentiated. May cause acute hypertensive crisis. |
|
| Phenylephrine with tricyclic anti-depressants. |
Pressor response increased. |
|
| Phenylephrine with ergot alkaloids. |
Excessive rise in blood pressure. |
|
| Phenylephrine with bronchodilator sympathomimetic agents and with epinephrine or other sympathomimetics. |
Tachycardia or other arrhythmias may occur. | |
| Phenylephrine with prior administration of propranolol or other β-adrenergic blockers. |
Cardiostimulating effects blocked. | |
| Phenylephrine with atropine sulfate. |
Reflex bradycardia blocked; pressor response enhanced. |
|
| Phenylephrine with prior administration of phentolamine or other α-adrenergic blockers. |
Pressor response decreased. | |
| Phenylephrine with diet preparations, such as amphetamines or phenylpropanolamine. |
Synergistic adrenergic response. |
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|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
|---|---|---|
| ↓= Decreased (induces lamotrigine glucuronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ? = Conflicting data. |
||
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine | Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide | ↓ lamotrigine | Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels. | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine | Increased lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. | |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
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| Amiodarone Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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| Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
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|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
|
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|
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
|
|
(mg/day) |
(mg/day) |
Concentration (Mean Change, 90% Confidence Interval) |
AED on MHD Concentration (Mean Change, 90% Confidence Interval) |
| Carbamazepine | 400-2000 | 900 | nc1 | 40% decrease [CI: 17% decrease, 57% decrease] |
| Phenobarbital | 100-150 | 600-1800 | 14% increase [CI: 2% increase, 24% increase] |
25% decrease [CI: 12% decrease, 51% decrease] |
| Phenytoin | 250-500 | 600-1800 >1200-2400 |
nc1,2
up to 40% increase3 [CI: 12% increase, 60% increase] |
30% decrease [CI: 3% decrease, 48% decrease] |
| Valproic acid | 400-2800 | 600-1800 | nc1 | 18% decrease [CI: 13% decrease, 40% decrease] |
|
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| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, gemfibrozil, cyclosporine,danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid grapefruit juice |
| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
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Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
|
|
Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C Protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) | Do not exceed 40 mg atorvastatin daily |
| Drug/Drug Class (Mechanism of Interaction by the Drug) |
Voriconazole Plasma Exposure (Cmax and AUCτ after 200 mg q12h) |
Recommendations for Voriconazole Dosage Adjustment/Comments |
|---|---|---|
| Rifampin (CYP450 Induction) |
Significantly Reduced |
|
| Efavirenz (CYP450 Induction) |
Significantly Reduced | When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg Q24h |
| High-dose Ritonavir (400 mg q12h) |
Significantly Reduced |
|
| Low-dose Ritonavir (100 mg q12h) |
Reduced | Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole |
| Carbamazepine (CYP450 Induction) |
Not Studied |
|
| Long Acting Barbiturates (CYP450 Induction) |
Not Studied |
|
| Phenytoin (CYP450 Induction) |
Significantly Reduced | Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg) |
| St. John's Wort (CYP450 inducer; P-gp inducer) |
Significantly Reduced |
|
| Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition) |
Increased | Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives |
| Fluconazole |
Significantly Increased | Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole. |
| Other HIV Protease Inhibitors (CYP3A4 Inhibition) |
|
No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir |
|
|
Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors | |
| Other NNRTIs (CYP3A4 Inhibition or CYP450 Induction) |
|
Frequent monitoring for adverse events and toxicity related to voriconazole |
| A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure) |
Careful assessment of voriconazole effectiveness |
| Drug/Drug Class (Mechanism of Interaction by Voriconazole) |
Drug Plasma Exposure (Cmax and AUCτ) |
Recommendations for Drug Dosage Adjustment/Comments |
|---|---|---|
| Sirolimus (CYP3A4 Inhibition) |
Significantly Increased |
|
| Rifabutin (CYP3A4 Inhibition) |
Significantly Increased |
|
| Efavirenz (CYP3A4 Inhibition) |
Significantly Increased | When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h |
| High-dose Ritonavir (400 mg q12h) |
No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ |
|
| Low-dose Ritonavir (100 mg q12h) |
Slight Decrease in Ritonavir Cmax and AUCτ | Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole |
| Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition) |
Not Studied |
|
| Ergot Alkaloids (CYP450 Inhibition) |
Not Studied |
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| Cyclosporine (CYP3A4 Inhibition) |
AUCτ Significantly Increased; No Significant Effect on Cmax | When initiating therapy with VFEND in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary. |
| Methadone |
Increased | Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed |
| Fentanyl (CYP3A4 Inhibition) | Increased | Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary [ |
| Alfentanil (CYP3A4 Inhibition) | Significantly Increased | Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [ |
| Oxycodone (CYP3A4 Inhibition) | Significantly Increased | Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary [ |
| NSAIDs (CYP2C9 Inhibition) |
Increased | Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [ |
| Tacrolimus (CYP3A4 Inhibition) |
Significantly Increased | When initiating therapy with VFEND in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary. |
| Phenytoin (CYP2C9 Inhibition) |
Significantly Increased | Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin. |
| Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition) |
Increased | Monitoring for adverse events related to oral contraceptives is recommended during coadministration. |
| Warfarin (CYP2C9 Inhibition) |
Prothrombin Time Significantly Increased | Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed. |
| Omeprazole (CYP2C19/3A4 Inhibition) |
Significantly Increased | When initiating therapy with VFEND in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors. |
| Other HIV Protease Inhibitors (CYP3A4 Inhibition) |
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No dosage adjustment for indinavir when coadministered with VFEND |
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(Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors | |
| Other NNRTIs (CYP3A4 Inhibition) |
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to NNRTI |
| Benzodiazepines (CYP3A4 Inhibition) |
(Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed. |
| HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition) |
(Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed. |
| Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition) |
(Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed. |
| Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition) |
Not Studied |
Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed. |
| Vinca Alkaloids (CYP3A4 Inhibition) |
Not Studied |
Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed. |
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| Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz*, nevirapine* |
↓ lopinavir | KALETRA dose increase is recommended in all patients Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz. KALETRA should not be administered once daily in combination with efavirenz or nevirapine |
| Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine |
↑ lopinavir | Appropriate doses of the combination with respect to safety and efficacy have not been established. |
| Nucleoside Reverse Transcriptase Inhibitor: didanosine |
KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food). |
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| Nucleoside Reverse Transcriptase Inhibitor: tenofovir |
↑ tenofovir | KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir. |
| Nucleoside Reverse Transcriptase Inhibitor: abacavir zidovudine |
↓ abacavir ↓ zidovudine |
KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown. |
| HIV-1 Protease Inhibitor: amprenavir* |
↑ amprenavir ↓ lopinavir |
KALETRA should not be administered once daily in combination with amprenavir |
| HIV-1 Protease Inhibitor: fosamprenavir/ritonavir |
↓ amprenavir ↓ lopinavir |
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor: indinavir* |
↑ indinavir | Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily |
| HIV-1 Protease Inhibitor: nelfinavir* |
↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir |
KALETRA should not be administered once daily in combination with nelfinavir |
| HIV-1 Protease Inhibitor: ritonavir* |
↑ lopinavir | Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor: saquinavir* |
↑ saquinavir | The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir. |
| HIV-1 Protease Inhibitor: tipranavir |
↓ lopinavir AUC and Cmin | KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily). |
| HIV CCR5 – Antagonist: maraviroc |
↑ maraviroc | Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry® (maraviroc). |
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| Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), quinidine |
↑ antiarrhythmics | Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA. |
| Anticancer Agents: vincristine, vinblastine, dasatinib, nilotinib |
↑ anticancer agents | Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents. For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions. |
| Anticoagulant: warfarin |
Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored. | |
| Anticonvulsants: carbamazepine, phenobarbital, phenytoin |
↓ lopinavir ↓ phenytoin |
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA. |
| Antidepressant: bupropion |
↓ bupropion ↓ active metabolite, hydroxybupropion |
Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion. |
| Antidepressant: trazodone |
↑ trazodone | Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered. |
| Anti-infective: clarithromycin |
↑ clarithromycin | For patients with renal impairment, the following dosage adjustments should be considered: • For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. • For patients with CLCR < 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary. |
| Antifungals: ketoconazole*, itraconazole, voriconazole |
↑ ketoconazole ↑ itraconazole ↓ voriconazole |
High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended. Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients. |
| Anti-gout: colchicine |
↑ colchicine | Patients with renal or hepatic impairment should not be given colchicine with KALETRA. 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). |
| Antimycobacterial: rifabutin* |
↑ rifabutin and rifabutin metabolite | Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary. |
| Antimycobacterial: rifampin |
↓ lopinavir | May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone |
| Antiparasitic: atovaquone |
↓ atovaquone | Clinical significance is unknown; however, increase in atovaquone doses may be needed. |
| Benzodiazepines: parenterally administered midazolam | ↑ midazolam | Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam |
| Calcium Channel Blockers: dihydropyridine, felodipine, nifedipine, nicardipine |
↑ dihydropyridine calcium channel blockers | Caution is warranted and clinical monitoring of patients is recommended. |
| Contraceptive: ethinyl estradiol* |
↓ ethinyl estradiol | Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended. |
| Corticosteroid: dexamethasone |
↓ lopinavir | Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly. |
| disulfiram/metronidazole | KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole). | |
| Endothelin Receptor Antagonists: bosentan |
↑ bosentan |
In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. |
| HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin |
↑ atorvastatin ↑ rosuvastatin |
Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day. See Drugs with No Observed or Predicted Interactions with KALETRA |
| Immunosuppressants: cyclosporine, tacrolimus, rapamycin |
↑ immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA. |
| Inhaled Steroid: fluticasone |
↑ fluticasone | Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect. |
| Long-acting beta-adrenoceptor Agonist: salmeterol |
↑ salmeterol | Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
| Narcotic Analgesic: methadone* fentanyl |
↓ methadone ↑ fentanyl |
Dosage of methadone may need to be increased when co-administered with KALETRA. Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA. |
| PDE5 inhibitors: sildenafil, tadalafil, vardenafil |
↑ sildenafil ↑ tadalafil ↑ vardenafil |
Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA The following dose adjustments are recommended for use of tadalafil (Adcirca®) with KALETRA: In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: It is recommended not to exceed the following doses: • Sildenafil: 25 mg every 48 hours • Tadalafil: 10 mg every 72 hours • Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events. |
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| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
|---|---|---|
| ↓= Decreased (induces lamotrigine glucuronidation). | ||
| ↑= Increased (inhibits lamotrigine glucuronidation). | ||
| ?= Conflicting data. | ||
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine | Decreased lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide | ↓ lamotrigine | Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels. | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
| Concomitant Drug |
Effect on Concentration of Lamotrigine or Concomitant Drug |
Clinical Comment |
| Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine ↓ levonorgestrel |
Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%. |
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Carbamazepine (CBZ) and CBZ epoxide |
↓ lamotrigine ? CBZ epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40% May increase CBZ epoxide levels |
| Phenobarbital/Primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40%. |
| Valproate |
↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
| Name of the Concomitant Drug | Change in the Concentration of Ganciclovir or Concomitant Drug | Clinical Comment |
|---|---|---|
| Zidovudine | ↓ Ganciclovir ↑ Zidovudine |
Zidovudine and Valcyte each have the potential to cause neutropenia and anemia |
| Probenecid | ↑ Ganciclovir | Patients taking probenecid and Valcyte should be monitored for evidence of ganciclovir toxicity |
| Mycophenolate Mofetil (MMF) | ↔ Ganciclovir (in patients with normal renal function) ↔ MMF (in patients with normal renal function) |
Patients with renal impairment should be monitored carefully as levels of MMF metabolites and ganciclovir may increase |
| Didanosine | ↓ Ganciclovir ↑ Didanosine |
Patients should be closely monitored for didanosine toxicity |
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| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, Posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, gemfibrozil, cyclosporine,danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
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| Amiodarone Iodide (including iodine- containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
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| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
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| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine,danazol | Do not exceed 10 mg simvastatindaily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Diltiazem | Do not exceed 40 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
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|||
| Digoxin Serum Concentration Increase | Digoxin AUC Increase |
|
|
| Amiodarone | 70% | NA | Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin dose by approximately 30% to 50% and continue monitoring. |
| Captopril | 58% | 39% | |
| Nitrendipine | 57% | 15% | |
| Propafenone | 35-85% | NA | |
| Quinidine | 100% | NA | |
| Ranolazine | 87% | 88% | |
| Ritonavir | NA | 86% | |
| Verapamil | 50-75% | NA | |
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|||
| Carvedilol | 16% | 14% | Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin dose by approximately 15% to 30% and continue monitoring. |
| Diltiazem | 20% | NA | |
| Nifedipine | 45% | NA | |
| Rabeprazole | 29% | 19% | |
| Telmisartan | 20% | NA | |
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| Alprazolam, Azithromycin, Clarithromycin, Cyclosporine, Diclofenac, Diphenoxylate, Epoprostenol, Erythromycin, Esomeprazole, Indomethacin, Itraconazole, Ketoconazole, Lansoprazole, Metformin, Omeprazole, Propantheline, Spironolactone, Tetracycline | Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary. | ||
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Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20% to 40% as necessary. | ||
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| Please refer to section 12.3 for a complete list of drugs which were studied but reported no significant changes on digoxin exposure. | No additional actions are required. | ||
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Dofetilide | Concomitant administration with digoxin was associated with a higher rate of torsades de pointes. |
| Moricizine | Reported to increase PR interval and QRS duration. There are reports of first degree atrioventricular block or bundle branch block developing with digitalis administration. The known effects of moricizine on calcium conductance may explain the effects on atrioventricular node conduction. | |
| Sotalol | Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin. | |
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Teriparatide | Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium. |
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Thyroid | Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin. |
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Epinepherine | Can increase the risk of cardiac arrhythmias. |
| Norepinephrine | ||
| Dopamine | ||
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Succinylcholine | May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin. |
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Calcium | If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients. |
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| Dopamine / Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day). |
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| Aminoglutethimide Amiodarone Iodide(including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
| |
|
| Amiodarone Iodide(including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
| |
|
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
| |
|
| |
|
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
| |
|
| Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4, and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
| |
|
| |
|
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
| |
|
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
| |
|
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms. |
| Interacting Drug | Interaction |
|---|---|
| Valproic acid | Doripenem reduced the serum concentrations of valproic acid to below the therapeutic concentration range in healthy subjects ( |
| Probenecid | Reduces renal clearance of doripenem, resulting in increased doripenem concentrations ( |
| Drugs metabolized by cytochrome P450 enzymes | Doripenem neither inhibits nor induces major cytochrome P450 enzymes ( |
| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
|
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir ) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) | Do not exceed 40 mg atorvastatin daily |
| ↓ = Decreased (induces lamotrigine gluronidation). ↑ = Increased (inhibits lamotrigine glucuronidation). ? = Conflicting data. |
||
| Concomitant Drug |
Effect on Concentration of Lamotrigine or Concomitant Drug |
Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine ↓ levonorgestrel |
Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%. |
| Carbamazepine (CBZ) and CBZ epoxide |
↓ lamotrigine ? CBZ epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase CBZ epoxide levels. |
| Phenobarbital/Primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40%. |
| Valproate |
↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
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|
|||
| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone Iodide (including iodine- containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
|
|
|||
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
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||
| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
|
|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
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|
|||
|
|
|||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
|
|
|||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
|
|
|||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
| albuterol, | famotidine | nizatidine |
| systemic and inhaled | felodipine | norfloxacin |
| amoxicillin | finasteride | ofloxacin |
| ampicillin, | hydrocortisone | omeprazole |
| with or without | isoflurane | prednisone, prednisolone |
| sulbactam | isoniazid | ranitidine |
| atenolol | isradipine | rifabutin |
| azithromycin | influenza vaccine | roxithromycin |
| caffeine, | ketoconazole | sorbitol |
| dietary ingestion | lomefloxacin | (purgative doses do not |
| cefaclor | mebendazole | inhibit theophylline |
| co-trimoxazole | medroxyprogesterone | absorption) |
| (trimethoprim and | methylprednisolone | sucralfate |
| sulfamethoxazole) | metronidazole | terbutaline, systemic |
| diltiazem | metoprolol | terfenadine |
| dirithromycin | nadolol | tetracycline |
| enflurane | nifedipine | tocainide |
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(mg) |
|
Pharmacokinetic Parameters (90% CI); No Effect = 1.00 |
||
| Cmax | AUC | Cmin | ||||
| All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated. | ||||||
| Cimetidine | 600 twice daily, 6 days |
400 single dose | 12 | 1.07 (0.77, 1.49) |
0.98 (0.81, 1.19) |
0.82 (0.69, 0.99) |
| Clarithromycin | 500 q12h, 7 days |
800 three times daily, 7 days |
10 | 1.08 (0.85, 1.38) |
1.19 (1.00, 1.42) |
1.57 (1.16, 2.12) |
| Delavirdine | 400 three times daily | 400 three times daily, 7 days |
28 | 0.64 (0.48, 0.86) |
No significant change |
2.18 (1.16, 4.12) |
| Delavirdine | 400 three times daily | 600 three times daily, 7 days |
28 | No significant change | 1.53 (1.07, 2.20) |
3.98 (2.04, 7.78) |
| Efavirenz |
600 once daily, 10 days |
1000 three times daily, 10 days |
20 | |||
| After morning dose | No significant change |
0.67 (0.61, 0.74) |
0.61 (0.49, 0.76) |
|||
| After afternoon dose | No significant change |
0.63 (0.54, 0.74) |
0.48 (0.43, 0.53) |
|||
| After evening dose | 0.71 (0.57, 0.89) |
0.54 (0.46, 0.63) |
0.43 (0.37, 0.50) |
|||
| Fluconazole |
400 once daily, 8 days |
1000 three times daily, 7 days | 11 | 0.87 (0.72, 1.05) |
0.76 (0.59, 0.98) |
0.90 (0.72, 1.12) |
| Grapefruit Juice | 8 oz. | 400 single dose | 10 | 0.65 (0.53, 0.79) |
0.73 (0.60, 0.87) |
0.90 (0.71, 1.15) |
| Isoniazid | 300 once daily in the morning, 8 days |
800 three times daily, 7 days | 11 | 0.95 (0.88, 1.03) |
0.99 (0.87, 1.13) |
0.89 (0.75, 1.06) |
| Itraconazole | 200 twice daily, 7 days |
600 three times daily, 7 days |
12 | 0.78 (0.69, 0.88) |
0.99 (0.91, 1.06) |
1.49 (1.28, 1.74) |
| Ketoconazole | 400 once daily, 7 days |
600 three times daily, 7 days |
12 | 0.69 (0.61, 0.78) |
0.80 (0.74, 0.87) |
1.29 (1.11, 1.51) |
| 400 once daily, 7 days |
400 three times daily, 7 days |
12 | 0.42 (0.37, 0.47) |
0.44 (0.41, 0.48) |
0.73 (0.62, 0.85) |
|
| Methadone | 20-60 once daily in the morning, 8 days |
800 three times daily, 8 days |
10 | See text below for discussion of interaction. | ||
| Quinidine | 200 single dose | 400 single dose | 10 | 0.96 (0.79, 1.18) |
1.07 (0.89, 1.28) |
0.93 (0.73, 1.19) |
| Rifabutin | 150 once daily in the morning, 10 days |
800 three times daily, 10 days |
14 | 0.80 (0.72, 0.89) |
0.68 (0.60, 0.76) |
0.60 (0.51, 0.72) |
| Rifabutin | 300 once daily in the morning, 10 days |
800 three times daily, 10 days |
10 | 0.75 (0.61, 0.91) |
0.66 (0.56, 0.77) |
0.61 (0.50, 0.75) |
| Rifampin | 600 once daily in the morning, 8 days |
800 three times daily, 7 days |
12 | 0.13 (0.08, 0.22) |
0.08 (0.06, 0.11) |
Not Done |
| Ritonavir | 100 twice daily, 14 days |
800 twice daily, 14 days |
10, 16 |
See text below for discussion of interaction. | ||
| Ritonavir | 200 twice daily, 14 days |
800 twice daily,14 days |
9, 16 |
See text below for discussion of interaction. | ||
| Sildenafil | 25 single dose | 800 three times daily | 6 | See text below for discussion of interaction. | ||
| St. John's wort ( standardized to 0.3 % hypericin) |
300 three times daily with meals, 14 days |
800 three times daily | 8 | Not Available | 0.46 (0.34, 0.58) |
0.19 (0.06, 0.33) |
| Stavudine (d4T) |
40 twice daily, 7 days |
800 three times daily, 7 days |
11 | 0.95 (0.80, 1.11) |
0.95 (0.80, 1.12) |
1.13 (0.83, 1.53) |
| Trimethoprim/ Sulfamethoxazole |
800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days |
400 four times daily, 7 days |
12 | 1.12 (0.87, 1.46) |
0.98 (0.81, 1.18) |
0.83 (0.72, 0.95) |
| Zidovudine |
200 three times daily, 7 days | 1000 three times daily, 7 days |
12 | 1.06 (0.91, 1.25) |
1.05 (0.86, 1.28) |
1.02 (0.77, 1.35) |
| Zidovudine/ Lamivudine (3TC) |
200/150 three times daily, 7 days | 800 three times daily, 7 days |
6, 9 |
1.05 (0.83, 1.33) |
1.04 (0.67, 1.61) |
0.98 (0.56, 1.73) |
|
|
|
|
|
Pharmacokinetic Parameters (90% CI); No Effect = 1.00 |
||
| Cmax | AUC | Cmin | ||||
| All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated. | ||||||
| Clarithromycin | 500 twice daily, 7 days |
800 three times daily, 7 days | 12 | 1.19 (1.02, 1.39) |
1.47 (1.30, 1.65) |
1.97 (1.58, 2.46) n=11 |
| Efavirenz | 200 once daily, 14 days |
800 three times daily, 14 days | 20 | No significant change | No significant change | -- |
| Ethinyl Estradiol (ORTHO-NOVUM 1/35) |
35 mcg, 8 days | 800 three times daily, 8 days | 18 | 1.02 (0.96, 1.09) |
1.22 (1.15, 1.30) |
1.37 (1.24, 1.51) |
| Isoniazid | 300 once daily in the morning, 8 days |
800 three times daily, 8 days | 11 | 1.34 (1.12, 1.60) |
1.12 (1.03, 1.22) |
1.00 (0.92, 1.08) |
| Methadone |
20-60 once daily in the morning, 8 days |
800 three times daily, 8 days | 12 | 0.93 (0.84, 1.03) |
0.96 (0.86, 1.06) |
1.06 (0.94, 1.19) |
| Norethindrone (ORTHO-NOVUM 1/35) |
1 mcg, 8 days | 800 three times daily, 8 days | 18 | 1.05 (0.95, 1.16) |
1.26 (1.20, 1.31) |
1.44 (1.32, 1.57) |
| Rifabutin 150 mg once daily in the morning, 11 days + indinavir compared to 300 mg once daily in the morning, 11 days alone |
150 once daily in the morning, 10 days 300 once daily in the morning, 10 days |
800 three times daily, 10 days 800 three times daily, 10 days |
14 10 |
1.29 (1.05, 1.59) 2.34 (1.64, 3.35) |
1.54 (1.33, 1.79) 2.73 (1.99, 3.77) |
1.99 (1.71, 2.31) n=13 3.44 (2.65, 4.46) n=9 |
| Ritonavir | 100 twice daily, 14 days |
800 twice daily, 14 days |
10, 4 |
1.61 (1.13, 2.29) |
1.72 (1.20, 2.48) |
1.62 (0.93, 2.85) |
| 200 twice daily, 14 days |
800 twice daily, 14 days |
9, 5 |
1.19 (0.85, 1.66) |
1.96 (1.39, 2.76) |
4.71 (2.66, 8.33) n=9, 4 |
|
| Saquinavir | ||||||
| Hard gel formulation | 600 single dose | 800 three times daily, 2 days | 6 | 4.7 (2.7, 8.1) |
6.0 (4.0, 9.1) |
2.9 (1.7, 4.7) |
| Soft gel formulation | 800 single dose | 800 three times daily, 2 days | 6 | 6.5 (4.7, 9.1) |
7.2 (4.3, 11.9) |
5.5 (2.2, 14.1) |
| Soft gel formulation | 1200 single dose | 800 three times daily, 2 days | 6 | 4.0 (2.7, 5.9) |
4.6 (3.2, 6.7) |
5.5 (3.7, 8.3) |
| Sildenafil | 25 single dose | 800 three times daily | 6 | See text below for discussion of interaction. | ||
| Stavudine |
40 twice daily, 7 days |
800 three times daily, 7 days | 13 | 0.86 (0.73, 1.03) |
1.21 (1.09, 1.33) |
Not Done |
| Theophylline | 250 single dose (on Days 1 and 7) | 800 three times daily, 6 days (Days 2 to 7) | 12, 4 |
0.88 (0.76, 1.03) |
1.14 (1.04, 1.24) |
1.13 (0.86, 1.49) n=7, 3 |
| Trimethoprim/ Sulfamethoxazole |
||||||
| Trimethoprim | 800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days |
400 q6h, 7 days | 12 | 1.18 (1.05, 1.32) |
1.18 (1.05, 1.33) |
1.18 (1.00, 1.39) |
| Trimethoprim/ Sulfamethoxazole |
||||||
| Sulfamethoxazole | 800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days |
400 q6h, 7 days | 12 | 1.01 (0.95, 1.08) |
1.05 (1.01, 1.09) |
1.05 (0.97, 1.14) |
| Vardenafil | 10 single dose | 800 three times daily | 18 | See text below for discussion of interaction. | ||
| Zidovudine |
200 three times daily, 7 days | 1000 three times daily, 7 days | 12 | 0.89 (0.73, 1.09) |
1.17 (1.07, 1.29) |
1.51 (0.71, 3.20) n=4 |
| Zidovudine/ Lamivudine |
||||||
| Zidovudine | 200/150 three times daily, 7 days | 800 three times daily, 7 days | 6, 7 |
1.23 (0.74, 2.03) |
1.39 (1.02, 1.89) |
1.08 (0.77, 1.50) n=5, 5 |
| Zidovudine/ Lamivudine |
||||||
| Lamivudine | 200/150 three times daily, 7 days | 800 three times daily, 7 days | 6, 7 |
0.73 (0.52, 1.02) |
0.91 (0.66, 1.26) |
0.88 (0.59, 1.33) |
|
|
Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel | ↓ lamotrigine | Decreased lamotrigine levels approximately 50%. |
| ↓levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide | ↓ lamotrigine | Addition of carbamazepine decreases lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels | |
| Phenobarbital/Primidone | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ lamotrigine | Decreased lamotrigine concentration approximately 40%. |
| Rifampin | ↓ lamotrigine | Decreased lamotrigine AUC approximately 40%. |
| Valproate | ↑ lamotrigine | Increased lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
| Drug |
Stavudine Dosage |
na |
AUC of Stavudine (95% CI) |
Cmax
of Stavudine (95% CI) |
|---|---|---|---|---|
|
↑ indicates increase ↔ indicates no change, or mean increase or decrease of greater then 10%. a HIV-infected patients. |
||||
|
Didanosine, 100 mg q12h for 4 days |
40 mg q12h for 4 days |
10 |
↔ |
↑17% |
|
Lamivudine, 150 mg single dose |
40 mg single dose |
18 |
↔ (92.7-100.6%) |
↑12% (100.3-126.1%) |
|
Nelfinavir, 750 mg q8h for 56 days |
30 to 40 mg q12h for 56 days |
8 |
↔ |
↔ |
| Drug | StavudineDosage | na |
AUC of Coadministered Drug (95% CI) |
Cmax
of Coadministered Drug (95% CI) |
|---|---|---|---|---|
|
↔ indicates no change, or mean increase or decrease of greater then 10%. a HIV-infected patients. |
||||
|
Didanosine, 100 mg q12h for 4 days |
40 mg q12h for 4 days |
10 |
↔ |
↔ |
|
Lamivudine, 150 mg single dose |
40 mg single dose |
18 |
↔ (90.5-107.6%) |
↔ (87.1-110.6%) |
|
Nelfinavir, 750 mg q8h for 56 days |
30 to 40 mg q12h for 56 days |
8 |
↔ |
↔ |
| *Results based on **Results based on *** Non-Nucleoside Reverse Transcriptase Inhibitors |
||
|
(Mechanism of Interaction by the Drug) |
(Cmax and AUC |
|
| Rifampin* and Rifabutin* (CYP450 Induction) |
Significantly Reduced |
|
| Efavirenz** (CYP450 Induction) |
Significantly Reduced | When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h |
|
|
|
|
| Low-dose Ritonavir (100 mg q12h)** (CYP450 Induction) |
|
|
| Carbamazepine (CYP450 Induction) |
Not Studied |
|
| Long Acting Barbiturates (CYP450 Induction) |
Not Studied |
|
| Phenytoin* (CYP450 Induction) |
Significantly Reduced | Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg) |
| St. John’s Wort (CYP450 inducer; P-gp inducer) |
Significantly Reduced |
|
| Oral Contraceptives** containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition) |
Increased | Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives |
| Fluconazole** (CYP2C9, CYP2C19 and CYP3A4 Inhibition) | Significantly Increased | Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole. |
| Other HIV Protease Inhibitors (CYP3A4 Inhibition) |
|
|
|
|
|
|
| A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure) | Careful assessment of voriconazole effectiveness | |
| *Results based on **Results based on *** Results based on **** Non-Steroidal Anti-Inflammatory Drug ***** Non-Nucleoside Reverse Transcriptase Inhibitors |
||
|
|
(Cmax and AUC |
|
| Sirolimus* (CYP3A4 Inhibition) |
Significantly Increased |
|
| Rifabutin* (CYP3A4 Inhibition) |
Significantly Increased |
|
| Efavirenz** (CYP3A4 Inhibition) |
Significantly Increased | When voriconazole is coadministeredwith efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h |
| High-dose Ritonavir (400 mg q12h)**(CYP3A4 Inhibition) | No Significant Effect of Voriconazole on |
|
| Ritonavir Cmax or AUCτ | ||
| Low-dose Ritonavir (100 mg q12h)** | Slight Decrease in Ritonavir Cmax and AUCτ | Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole |
| Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition) | Not Studied |
|
| Ergot Alkaloids (CYP450 Inhibition) |
Not Studied |
|
| Cyclosporine* (CYP3A4 Inhibition) |
AUCτ Significantly Increased; No Significant Effect on Cmax | When initiating therapy with voriconazole tablets in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole tablets are discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary. |
| Methadone*** (CYP3A4 Inhibition) |
Increased | Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed |
| Fentanyl (CYP3A4 Inhibition) |
Increased | Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole tablets. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see |
| Alfentanil (CYP3A4 Inhibition) |
Significantly Increased | Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole tablets. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see |
| Oxycodone (CYP3A4 Inhibition) |
Significantly Increased | Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole tablets. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see |
|
|
Increased | Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed. [see |
|
|
Significantly Increased | When initiating therapy with voriconazole tablets in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole tablets are discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary. |
|
|
Significantly Increased | Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin. |
| Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)** | Increased | Monitoring for adverse events related to oral contraceptives is recommended during coadministration. |
|
|
Prothrombin Time Significantly Increased | Monitor PT or other suitable anticoagulation tests. Adjustment of warfarin dosage may be needed. |
|
|
Significantly Increased | When initiating therapy with voriconazole tablets in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors. |
| Other HIV Protease Inhibitors |
|
No dosage adjustment for indinavir |
| (CYP3A4 Inhibition) |
|
|
|
|
Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors | |
|
|
|
Frequent monitoring for adverse events and toxicity related to NNRTI |
|
|
|
Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed. |
| HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition) |
|
Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed. |
|
|
|
Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed. |
| Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition) | Not Studied |
Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed. |
|
|
Not Studied |
Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed. |
|
|
|
|
|
|
||
| Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz*, nevirapine* |
↓ lopinavir | KALETRA dose increase is recommended in all patients Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz. KALETRA should not be administered once daily in combination with efavirenz or nevirapine |
| Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine |
↑ lopinavir | Appropriate doses of the combination with respect to safety and efficacy have not been established. |
| Nucleoside Reverse Transcriptase Inhibitor: didanosine |
KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food). |
|
| Nucleoside Reverse Transcriptase Inhibitor: tenofovir |
↑ tenofovir | KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir. |
| Nucleoside Reverse Transcriptase Inhibitor: abacavir zidovudine |
↓ abacavir ↓ zidovudine |
KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown. |
| HIV-1 Protease Inhibitor: amprenavir* |
↑ amprenavir ↓ lopinavir |
KALETRA should not be administered once daily in combination with amprenavir |
| HIV-1 Protease Inhibitor: fosamprenavir/ritonavir |
↓ amprenavir ↓ lopinavir |
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor: indinavir* |
↑ indinavir | Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily |
| HIV-1 Protease Inhibitor: nelfinavir* |
↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir |
KALETRA should not be administered once daily in combination with nelfinavir |
| HIV-1 Protease Inhibitor: ritonavir* |
↑ lopinavir | Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor: saquinavir* |
↑ saquinavir | The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir. |
| HIV-1 Protease Inhibitor: tipranavir |
↓ lopinavir AUC and Cmin | KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily). |
| HIV CCR5 – antagonist: maraviroc | ↑ maraviroc | Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry® (maraviroc). |
|
|
||
| Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), and quinidine |
↑ antiarrhythmics | Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA. |
| Anticancer Agents: vincristine, vinblastine, dasatinib, nilotinib |
↑ anticancer agents | Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents. For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions. |
| Anticoagulant: warfarin |
Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored. | |
| Anticonvulsants: carbamazepine, phenobarbital, phenytoin |
↓ lopinavir ↓ phenytoin |
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA. |
| Antidepressant: bupropion |
↓ bupropion ↓ active metabolite, hydroxybupropion |
Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion. |
| Antidepressant: trazodone |
↑ trazodone | Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered. |
| Anti-infective: clarithromycin |
↑ clarithromycin | For patients with renal impairment, the following dosage adjustments should be considered: • For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. • For patients with CLCR < 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary. |
| Antifungals: ketoconazole*, itraconazole, voriconazole |
↑ ketoconazole ↑ itraconazole ↓ voriconazole |
High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended. Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients. |
| Anti-gout: colchicine |
↑ colchicine | Patients with renal or hepatic impairment should not be given colchicine with KALETRA. 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). |
| Antimycobacterial: rifabutin* |
↑ rifabutin and rifabutin metabolite | Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary. |
| Antimycobacterial: rifampin |
↓ lopinavir | May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone |
| Antiparasitic: atovaquone |
↓ atovaquone | Clinical significance is unknown; however, increase in atovaquone doses may be needed. |
| Benzodiazepines: parenterally administered midazolam | ↑ midazolam | Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam |
| Calcium Channel Blockers, dihydropyridine: e.g., felodipine, nifedipine, nicardipine |
↑ dihydropyridine calcium channel blockers | Caution is warranted and clinical monitoring of patients is recommended. |
| Contraceptive: ethinyl estradiol* |
↓ ethinyl estradiol | Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended. |
| Corticosteroid: dexamethasone |
↓ lopinavir | Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly. |
| disulfiram/metronidazole | KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole). | |
| Endothelin receptor antagonists: bosentan |
↑ bosentan |
In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability. |
| HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin |
↑ atorvastatin ↑ rosuvastatin |
Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with KALETRA. |
| Immunosuppressants: cyclosporine, tacrolimus, rapamycin |
↑ immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA. |
| Inhaled Steroid: fluticasone |
↑ fluticasone | Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect. |
| Long-acting beta-adrenoceptor agonist: salmeterol |
↑ salmeterol | Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
| Narcotic Analgesic: methadone* fentanyl |
↓ methadone ↑ fentanyl |
Dosage of methadone may need to be increased when co-administered with KALETRA. Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA. |
| PDE5 inhibitors: sildenafil, tadalafil, vardenafil |
↑ sildenafil ↑ tadalafil ↑ vardenafil |
Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA The following dose adjustments are recommended for use of tadalafil (Adcirca®) with KALETRA: In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: It is recommended not to exceed the following doses: • Sildenafil: 25 mg every 48 hours • Tadalafil: 10 mg every 72 hours • Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events. |
| * |
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|
(Peak plasma concentration) |
(Extent of systemic exposure) |
| Erythromycin (500 mg every 8 hrs) |
+82% | +109% |
| Ketoconazole (400 mg once daily) |
+135% | +164% |
| Concomitant Drug Class: Drug Name |
Effect on Concentration of Raltegravir | Clinical Comment |
|---|---|---|
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| atazanavir | ↑ | Atazanavir, a strong inhibitor of UGT1A1, increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended. |
| atazanavir/ritonavir | ↑ | Atazanavir/ritonavir increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended. |
| efavirenz | ↓ | Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed. |
| etravirine | ↓ | Etravirine reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed. |
| tipranavir/ritonavir | ↓ | Tipranavir/ritonavir reduces plasma concentrations of raltegravir. However, since comparable efficacy was observed for this combination relative to other ISENTRESS-containing regimens in Phase 3 studies 018 and 019, no dose adjustment is recommended. |
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| omeprazole | ↑ | Coadministration of medicinal products that increase gastric pH (e.g., omeprazole) may increase raltegravir levels based on increased raltegravir solubility at higher pH. However, since concomitant use of ISENTRESS with proton pump inhibitors and H2 blockers did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended. |
| rifampin | ↓ | Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of raltegravir. The recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin. |
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine | Do not exceed 10 mg atorvastatin daily |
| Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir) | Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used. |
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| Phenytoin |
NC or 25% increasea
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48% decrease |
| Carbamazepine (CBZ) |
NC |
40% decrease |
| CBZ epoxideb
|
NC |
NE |
| Valproic acid |
11% decrease |
14% decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NC at TPM doses up to 400 mg/day |
13% decrease |
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| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
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Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
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Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
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Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
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- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function. |
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Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4 . Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
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Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
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Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
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- Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
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- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
|
- Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
|
- Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
|
- Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
|
- (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
|
Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
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| Table 5 Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours in healthy adult subjects (n=24) | ||
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(Peak plasma concentration) |
(Extent of systemic exposure) |
| Erythromycin (500 mg every 8 hrs) |
+82% | +109% |
| Ketoconazole (400 mg once daily) |
+135% | +164% |
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| DRUG | DESCRIPTION OF INTERACTION | ||
| Sulfonylureas | Hypoglycemia potentiated. | ||
| Methotrexate | Decreases tubular reabsorption; clinical toxicity from methotrexate can result. | ||
| Oral Anticoagulants | Increased bleeding. | ||
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| DRUG | DESCRIPTION OF INTERACTION | ||
| Corticosteroids | Decreases plasma salicylate level; tapering doses of steroids may promote salicylism. | ||
| Acidifying Agents | Increases plasma salicylate levels. | ||
| Alkanizing Agents | Decreased plasma salicylate levels. | ||
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| DRUG | DESCRIPTION OF INTERACTION | ||
| Heparin | Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients. | ||
| Pyrazinamide | Inhibits pyrazinamide-induced hyperuricemia. | ||
| Uricosuric Agents | Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited. | ||
| The following alterations of laboratory tests have been reported during salicylate therapy: | |||
| LABORATORY TESTS | EFFECT OF SALICYLATES | ||
| Thyroid Function | Decreased PBI; increased t3 uptake. | ||
| Urinary Sugar | False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.). | ||
| 5-Hydroxyindole acetic acid | False negative with fluorometric test. | ||
| Acetone ketone bodies | False positive FeCI3 in Gerhardt reaction; red color persists with boiling. | ||
| 17-OH corticosteroids | False reduced values with >4.8g q.d. salicylate. | ||
| Vanilmandelic acid | False reduced values. | ||
| Uric Acid | May increase or decrease depending on dose. | ||
| Prothrombin | Decreased levels; slightly increased prothrombin time. | ||
|
|
(mg/day) |
(mg/day) |
Concentration (Mean Change, 90% Confidence Interval) |
AED on MHD Concentration (Mean Change, 90% Confidence Interval) |
| Carbamazepine | 400-2000 | 900 | nc1 | 40% decrease [CI: 17% decrease, 57% decrease] |
| Phenobarbital | 100-150 | 600-1800 | 14% increase [CI: 2% increase, 24% increase] |
25% decrease [CI: 12% decrease, 51% decrease] |
| Phenytoin | 250-500 | 600-1800 >1200-2400 |
nc1,2
up to 40% increase3 [CI: 12% increase, 60% increase] |
30% decrease [CI: 3% decrease, 48% decrease] |
| Valproic acid | 400-2800 | 600-1800 | nc1 | 18% decrease [CI: 13% decrease, 40% decrease] |
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| Enzyme | Inhibitors | Inducers |
|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
| Drug Class | Specific Drugs |
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
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Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid grapefruit juice |
| Concomitant Drug Class: Drug Name |
Effect on Concentration |
Clinical Comment |
|---|---|---|
| HIV Antiviral Agents: Reverse Transcriptase Inhibitors | ||
| Delavirdine | ↑ nelfinavir (Cmin) ↓ delavirdine |
Concentrations of nelfinavir were increased while concentrations of delavirdine were decreased when the two agents were coadministered. Appropriate doses of the combination, with respect to safety and efficacy, have not been established. |
| Nevirapine | ↓ nelfinavir (Cmin) | Concentrations of nelfinavir were decreased when coadministered with nevirapine. An appropriate dose of nelfinavir with respect to safety and efficacy has not been established. |
| Didanosine | ↔ nelfinavir | There was no change in nelfinavir concentration when coadministered with didanosine. However, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after VIRACEPT (given with food). |
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| Indinavir | ↑ nelfinavir ↑ indinavir |
Concentrations of both indinavir and nelfinavir were increased when the two agents were coadministered. Appropriate doses for these combinations, with respect to safety and efficacy, have not been established. |
| Ritonavir | ↑ nelfinavir ↔ ritonavir |
Concentrations of nelfinavir were increased when coadministered with ritonavir. An appropriate dose of nelfinavir for this combination, with respect to safety and efficacy, has not been established. |
| Saquinavir | ↑ nelfinavir ↑ saquinavir |
Concentrations of both saquinavir and nelfinavir were increased when the two agents were coadministered. Appropriate doses for these combinations, with respect to safety and efficacy, have not been established. |
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| Warfarin | Warfarin | Coadministration of warfarin and VIRACEPT may affect concentrations of warfarin. It is recommended that the INR (international normalized ratio) be monitored carefully during treatment with VIRACEPT, especially when commencing therapy. |
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| Carbamazepine Phenobarbital Phenytoin |
↓ nelfinavir ↓ phenytoin |
Concentrations of nelfinavir may be decreased. VIRACEPT may not be effective due to decreased nelfinavir plasma concentrations in patients taking these agents concomitantly. Phenytoin plasma/serum concentrations should be monitored; phenytoin dose may require adjustment to compensate for altered phenytoin concentration. |
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| Trazodone | ↑ trazodone | Concomitant use of trazodone and VIRACEPT may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as VIRACEPT, the combination should be used with caution and a lower dose of trazodone should be considered. |
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| Colchicine | ↑ colchicines | Patients with renal or hepatic impairment should not be given colchicine with VIRACEPT due to the risk of colchicine toxicity. Treatment of gout flares – co- administration of colchicine in patients on VIRACEPT: 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout-flares – coadministration of colchicine in patients on VIRACEPT: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF)– coadministration of colchicine in patients on VIRACEPT: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). |
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| Rifabutin | ↑ rifabutin ↓ nelfinavir (750 mg TID) ↔ nelfinavir (1250 mg BID) |
It is recommended that the dose of rifabutin be reduced to one-half the usual dose when administered with VIRACEPT; 1250 mg BID is the preferred dose of VIRACEPT when coadministered with rifabutin. |
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| Bosentan | ↑ bosentan | Concentrations of bosentan may be increased when coadministered with VIRACEPT. Coadministration of bosentan in patients on VIRACEPT or coadministration of VIRACEPT in patients on bosentan: Start at or adjust bosentan to 62.5 mg once daily or every other day based upon individual tolerability. |
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| Atorvastatin Rosuvastatin |
↑ atorvastatin ↑ rosuvastatin |
Titrate atorvastatin dose carefully and use the lowest necessary dose; do not exceed atorvastatin 40 mg/day. |
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| Cyclosporine Tacrolimus Sirolimus |
↑ immuno-suppressants ↑ nelfinavir |
Concentrations of these immunosuppressants and nelfinavir may be increased by coadministration of these agents with nelfinavir. |
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| Salmeterol | ↑ salmeterol | Concurrent administration of salmeterol with VIRACEPT is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
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| Fluticasone | ↑ fluticasone | Concomitant use of fluticasone propionate and VIRACEPT may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use. |
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| Azithromycin | ↑ azithromycin | Dose adjustment of azithromycin is not recommended, but close monitoring for known side effects such as liver enzyme abnormalities and hearing impairment is warranted. |
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| Methadone | ↓ methadone | Concentrations of methadone were decreased when coadministered with VIRACEPT. Dosage of methadone may need to be increased when coadministered with VIRACEPT. |
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| Ethinyl estradiol Norethindrone |
↓ ethinyl estradiol ↓ norethindrone |
Concentrations of ethinyl estradiol and norethindrone were decreased when coadministered with VIRACEPT. Alternative or additional contraceptive measures should be used when oral contraceptives containing ethinyl estradiol or norethindrone and VIRACEPT are coadministered. |
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| Sildenafil Vardenafil Tadalafil |
↑ PDE5 Inhibitors | Concomitant use of PDE5 inhibitors and VIRACEPT should be undertaken with caution. May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. • Use of sildenafil (REVATIO) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [ • The following dose adjustments are recommended for use of tadalafil (ADCIRCA™) with VIRACEPT: Start at or adjust ADCIRCA to 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 24 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours, is recommended. Use with increased monitoring for adverse events. |
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| Omeprazole | ↓ nelfinavir | Omeprazole decreases the plasma concentrations of nelfinavir. Concomitant use of proton pump inhibitors and VIRACEPT may lead to a loss of virologic response and development of resistance. |
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| DRUG | DESCRIPTION OF INTERACTION | ||
| Sulfonylureas | Hypoglycemia potentiated. | ||
| Methotrexate | Decreases tubular reabsorption; clinical toxicity from methotrexate can result. | ||
| Oral Anticoagulants | Increased bleeding. | ||
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| DRUG | DESCRIPTION OF INTERACTION | ||
| Corticosteroids | Decreases plasma salicylate level; tapering doses of steroids may promote salicylism. | ||
| Acidifying Agents | Increases plasma salicylate levels. | ||
| Alkanizing Agents | Decreased plasma salicylate levels. | ||
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| DRUG | DESCRIPTION OF INTERACTION | ||
| Heparin | Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients. | ||
| Pyrazinamide | Inhibits pyrazinamide-induced hyperuricemia. | ||
| Uricosuric Agents | Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited. | ||
| The following alterations of laboratory tests have been reported during salicylate therapy: | |||
| LABORATORY TESTS | EFFECT OF SALICYLATES | ||
| Thyroid Function | Decreased PBI; increased t3 uptake. | ||
| Urinary Sugar | False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.). | ||
| 5-Hydroxyindole acetic acid | False negative with fluorometric test. | ||
| Acetone ketone bodies | False positive FeCI3 in Gerhardt reaction; red color persists with boiling. | ||
| 17-OH corticosteroids | False reduced values with >4.8g q.d. salicylate. | ||
| Vanilmandelic acid | False reduced values. | ||
| Uric Acid | May increase or decrease depending on dose. | ||
| Prothrombin | Decreased levels; slightly increased prothrombin time. | ||
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
|
Decreased Lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide |
|
Addition of carbamazepine decreases Lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels. | |
| Phenobarbital/Primidone | ↓ Lamotrigine | Decreased Lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ Lamotrigine | Decreased Lamotrigine concentration approximately 40%. |
| Rifampin | ↓ Lamotrigine | Decreased Lamotrigine AUC approximately 40%. |
| Valproate |
|
Increased Lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
|
|
|
| Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents). | Quinine sulfate prolongs QT interval, ECG abnormalities including QT prolongation and torsade de pointes. Avoid concomitant use ( |
| Other antimalarials (e.g., halofantrine, mefloquine). | ECG abnormalities including QT prolongation. Avoid concomitant use ( |
| CYP3A4 inducers or inhibitors | Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine ( |
| CYP3A4 and CYP2D6 substrates | Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the coadministered drug ( |
| Digoxin | Increased digoxin plasma concentration ( |
|
|
|
||
|
|
|||
| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
|
|
|||
|
|
|||
| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
|
|
|||
|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
| |
|||
|
|
|
||
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
||
|
|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
| |
|||
| |
|||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
|
|
|||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
|
|
|||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
|
|
|
|
|
|
||
|
|
||
|
|
||
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine |
Decreased lamotrigine levels approximately 50% |
|
|
↓ levonorgestrel |
Decrease in levonorgestrel component by 19% |
| Carbamazepine (CBZ) and CBZ epoxide |
↓ lamotrigine |
Addition of carbamazepine decreases lamotrigine concentration approximately 40% |
|
|
? CBZ epoxide |
May increase CBZ epoxide levels. |
| Phenobarbital/Primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40% |
| Phenytoin (PHT) |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40% |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40% |
| Valproate |
↑ lamotrigine |
Increased lamotrigine concentrations slightly more than 2-fold |
|
|
? valproate |
Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
|
|
|
||
|
|
|||
| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
|
|
|||
|
|
|||
| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone Iodide (including iodine- containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
|
|
|||
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
|
|
|||
|
|
|
||
|
|
|
||
| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
|
|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
|
|
|||
|
|
|||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
|
|
|||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
|
|
|||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
|
|
||
| Concomitant Drug |
Effect on Concentration of Lamotrigine or Concomitant Drug |
Clinical Comment |
| Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine ↓ levonorgestrel |
Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%. |
| Carbamazepine (CBZ) and CBZ epoxide |
↓ lamotrigine ? CBZ epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase CBZ epoxide levels |
| Phenobarbital/Primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40%. |
| Valproate |
↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
|
|
|
|
|
| ciprofloxacin | melphalan | azapropazon | cimetidine |
| gentamicin | colchicine | ranitidine | |
| tobramycin |
|
diclofenac | |
| vancomycin | amphotericin B | naproxen |
|
| trimethoprim with sulfamethoxazole | ketoconazole | sulindac | tacrolimus |
|
|
|||
| fibric acid derivatives | |||
| (e.g.,bezafibrate, fenofibrate) methotrexate |
|
|
|
|
|
|
| diltiazem | fluconazole | azithromycin | methylprednisolone | allopurinol |
| nicardipine | itraconazole | clarithromycin | amiodarone | |
| verapamil | ketoconazole | erythromycin | bromocriptine | |
| voriconazole | quinupristin/ | colchicine | ||
| dalfopristin | danazol | |||
| imatinib | ||||
| metoclopramide | ||||
| nefazodone | ||||
| oral contraceptives |
|
|
|
|
| nafcillin | carbamazepine | bosentan |
| rifampin | oxcarbazepine | octreotide |
| phenobarbital | orlistat | |
| phenytoin | sulfinpyrazone | |
| St. John's Wort | ||
| terbinafine | ||
| ticlopidine |
| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
|
| Interacting Agents | Prescribing Recommendations |
| Strong CYP3A inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, and nefazodone), Erythromycin | Contraindicated with lovastatin |
| Gemfibrozil, cyclosporine | Avoid with lovastatin |
| Danazol, diltiazem, dronedarone, verapamil | Do not exceed 20 mg lovastatin daily |
| Amiodarone | Do not exceed 40 mg lovastatin daily |
| Grapefruit juice | Avoid grapefruit juice |
|
|
|
|
|
|
|
Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
|
|
|
|
|
|
|
Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
|
|
|
|
Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
|
|
|
|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function. |
|
|
|
|
|
|
|
Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
|
Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4 . Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
|
|
|
|
|
|
|
Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
|
|
|
|
Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
|
|
|
|
- Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
|
- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
|
- Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
|
- Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
|
- Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
|
- (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
|
Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
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| CYP2C9 |
amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast |
aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 |
acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton |
montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 |
alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton |
armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
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| Anticoagulants |
argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents |
aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents |
celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors |
citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
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| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine,danazol | Do not exceed 10 mg simvastatindaily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Diltiazem | Do not exceed 40 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
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| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
| *Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects **Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects *** Non-Nucleoside Reverse Transcriptase Inhibitors |
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(CYP450 inducer; P-gp inducer) |
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containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition) |
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(CYP3A4 Inhibition) |
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| *Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects **Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects *** Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30 to 100 mg QD) **** Non-Steroidal Anti-Inflammatory Drug ***** Non-Nucleoside Reverse Transcriptase Inhibitors |
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| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. ( |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents |
Carefully monitor blood glucose ( |
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| Multivalent cation-containing products including antacids, metal cations or didanosine | Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
| Concomitant Drug Class: Drug Name |
Effect on concentration of INCIVEK or Concomitant Drug | Clinical Comment |
|---|---|---|
| The direction of the arrow (↑ |
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| lidocaine (systemic), amiodarone, bepridil, flecainide, propafenone, quinidine |
↑ antiarrhythmics | Co-administration with telaprevir has the potential to produce serious and/or life-threatening adverse events and has not been studied. Caution is warranted and clinical monitoring is recommended when co-administered with telaprevir. |
| digoxin |
↑ digoxin |
Concentrations of digoxin were increased when co-administered with telaprevir. The lowest dose of digoxin should be initially prescribed. The serum digoxin concentrations should be monitored and used for titration of digoxin dose to obtain the desired clinical effect. |
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| clarithromycin erythromycin telithromycin |
↑ telaprevir ↑ antibacterials |
Concentrations of both telaprevir and the antibacterial may be increased during co-administration. Caution is warranted and clinical monitoring is recommended when co-administered with telaprevir. QT interval prolongation and Torsade de Pointes have been reported with clarithromycin and erythromycin. QT interval prolongation has been reported with telithromycin. |
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| warfarin | ↑ or ↓ warfarin | Concentrations of warfarin may be altered when co-administered with telaprevir. The international normalized ratio (INR) should be monitored when warfarin is co-administered with telaprevir. |
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| carbamazepine phenobarbital phenytoin |
↓ telaprevir ↑ carbamazepine ↑ or ↓ phenytoin ↑ or ↓ phenobarbital |
Concentrations of the anticonvulsant may be altered and concentrations of telaprevir may be decreased. Caution should be used when prescribing carbamazepine, phenobarbital, and phenytoin. Telaprevir may be less effective in patients taking these agents concomitantly. Clinical or laboratory monitoring of carbamazepine, phenobarbital, and phenytoin concentrations and dose titration are recommended to achieve the desired clinical response. |
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| escitalopram |
↔ telaprevir ↓ escitalopram |
Concentrations of escitalopram were decreased when co-administered with telaprevir. Selective serotonin reuptake inhibitors such as escitalopram have a wide therapeutic index, but doses may need to be adjusted when combined with telaprevir. |
| trazodone | ↑ trazodone | Concomitant use of trazodone and telaprevir may increase plasma concentrations of trazodone which may lead to adverse events such as nausea, dizziness, hypotension and syncope. If trazodone is used with telaprevir, the combination should be used with caution and a lower dose of trazodone should be considered. |
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| ketoconazole itraconazole posaconazole voriconazole |
↑ ketoconazole ↑ telaprevir ↑ itraconazole ↑ posaconazole ↑ or ↓ voriconazole |
Ketoconazole increases the plasma concentrations of telaprevir. Concomitant systemic use of itraconazole or posaconazole with telaprevir may increase plasma concentration of telaprevir. Plasma concentrations of itraconazole, ketoconazole, or posaconazole may be increased in the presence of telaprevir. When co-administration is required, high doses of itraconazole or ketoconazole (greater than 200 mg/day) are not recommended. |
| Caution is warranted and clinical monitoring is recommended for itraconazole, posaconazole and voriconazole. | ||
| QT interval prolongation and Torsade de Pointes have been reported with voriconazole and posaconazole. QT interval prolongation has been reported with ketoconazole. Due to multiple enzymes involved with voriconazole metabolism, it is difficult to predict the interaction with telaprevir. Voriconazole should not be administered to patients receiving telaprevir unless an assessment of the benefit/risk ratio justifies its use. |
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| colchicine | ↑ colchicine | Patients with renal or hepatic impairment should not be given colchicine with telaprevir, due to the risk of colchicine toxicity. A reduction in colchicine dosage or an interruption of colchicine treatment is recommended in patients with normal renal or hepatic function. 0.6 mg (1 tablet) for 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Not to be repeated before 3 days. If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). |
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| rifabutin | ↓ telaprevir ↑ rifabutin |
Concentrations of telaprevir may be decreased, while rifabutin concentrations may be increased during co-administration. Telaprevir may be less effective due to decreased concentrations. The concomitant use of rifabutin and telaprevir is not recommended. |
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| alprazolam |
↑ alprazolam | Concomitant use of alprazolam and telaprevir increases exposure to alprazolam. Clinical monitoring is warranted. |
| parenterally administered midazolam |
↑ midazolam | Concomitant use of parenterally administered midazolam with telaprevir increased exposure to midazolam. Co-administration should be done in a setting which ensures clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dose reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. |
| Co-administration of oral midazolam with telaprevir is contraindicated. | ||
| zolpidem (non-benzodiazepine sedative) |
↓ zolpidem | Exposure to zolpidem was decreased when co-administered with telaprevir. Clinical monitoring and dose titration of zolpidem is recommended to achieve the desired clinical response. |
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| amlodipine |
↑ amlodipine | Exposure to amlodipine was increased when co-administered with telaprevir. Caution should be used and dose reduction for amlodipine should be considered. Clinical monitoring is recommended. |
| diltiazem felodipine nicardipine nifedipine nisoldipine verapamil |
↑calcium channel blockers | Concentrations of other calcium channel blockers may be increased when telaprevir is co-administered. Caution is warranted and clinical monitoring of patients is recommended. |
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|
prednisone methylprednisolone |
↑ prednisone ↑ methylprednisolone |
Systemic corticosteroids such as prednisone and methylprednisolone are CYP3A substrates. Since telaprevir is a strong CYP3A inhibitor, plasma concentrations of these corticosteroids can be increased significantly. Co-administration of systemic corticosteroids and telaprevir is not recommended [ |
|
dexamethasone |
↓ telaprevir |
Systemic dexamethasone induces CYP3A and can thereby decrease telaprevir plasma concentrations. This may result in loss of therapeutic effect of telaprevir. Therefore this combination should be used with caution or alternatives should be considered. |
|
fluticasone budesonide |
↑fluticasone ↑ budesonide |
Concomitant use of inhaled fluticasone or budesonide and telaprevir may increase plasma concentrations of fluticasone or budesonide resulting in significantly reduced serum cortisol concentrations. Co-administration of fluticasone or budesonide and telaprevir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. |
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| bosentan | ↑ bosentan | Concentrations of bosentan may be increased when co-administered with telaprevir. Caution is warranted and clinical monitoring is recommended. |
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| atazanavir/ritonavir |
↓ telaprevir ↑ atazanavir |
Concomitant administration of telaprevir and atazanavir/ritonavir resulted in reduced steady-state telaprevir exposure, while steady-state atazanavir exposure was increased. |
| darunavir/ritonavir |
↓ telaprevir ↓ darunavir |
Concomitant administration of telaprevir and darunavir/ritonavir resulted in reduced steady-state exposures to telaprevir and darunavir. It is not recommended to co-administer darunavir/ritonavir and telaprevir. |
| fosamprenavir/ritonavir |
↓ telaprevir ↓ fosamprenavir |
Concomitant administration of telaprevir and fosamprenavir/ritonavir resulted in reduced steady-state exposures to telaprevir and amprenavir. It is not recommended to co-administer fosamprenavir/ritonavir and telaprevir. |
| lopinavir/ritonavir |
↓ telaprevir ↔ lopinavir |
Concomitant administration of telaprevir and lopinavir/ritonavir resulted in reduced steady-state telaprevir exposure, while the steady-state exposure to lopinavir was not affected. It is not recommended to co-administer lopinavir/ritonavir and telaprevir. |
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| efavirenz |
↓ telaprevir ↓ efavirenz |
Concomitant administration of telaprevir and efavirenz resulted in reduced steady-state exposures to telaprevir and efavirenz. |
| tenofovir disoproxil fumarate |
↔ telaprevir ↑ tenofovir |
Concomitant administration of telaprevir and tenofovir disoproxil fumarate resulted in increased tenofovir exposure. Increased clinical and laboratory monitoring are warranted. Tenofovir disoproxil fumarate should be discontinued in patients who develop tenofovir-associated toxicities. |
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| atorvastatin fluvastatin pitavastatin pravastatin rosuvastatin |
↑ statin | Plasma concentrations of atorvastatin are markedly increased when co-administered with telaprevir. Avoid concomitant administration of telaprevir and atorvastatin. For fluvastatin, pitavastatin, pravastatin, and rosuvastatin, caution is warranted and clinical monitoring is recommended. Refer to |
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| ethinyl estradiol norethindrone |
↓ ethinyl estradiol ↔ norethindrone |
Exposure to ethinyl estradiol was decreased when co-administered with telaprevir. Two effective non-hormonal methods of contraception should be used during treatment with telaprevir. Patients using estrogens as hormone replacement therapy should be clinically monitored for signs of estrogen deficiency. Refer also to |
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| cyclosporine sirolimus tacrolimus |
↑ cyclosporine ↑ sirolimus ↑ tacrolimus |
Plasma concentrations of cyclosporine and tacrolimus are markedly increased when co-administered with telaprevir. Plasma concentration of sirolimus may be increased when co-administered with telaprevir, though this has not been studied. Significant dose reductions and prolongation of the dosing interval of the immunosuppressant to achieve the desired blood levels should be anticipated. Close monitoring of the immunosuppressant blood levels, and frequent assessments of renal function and immunosuppressant-related side effects are recommended when co-administered with telaprevir. Tacrolimus may prolong the QT interval. The use of telaprevir in organ transplant patients has not been studied. |
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| salmeterol | ↑ salmeterol | Concentrations of salmeterol may be increased when co-administered with telaprevir. Concurrent administration of salmeterol and telaprevir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. |
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| repaglinide | ↑ repaglinide | Caution is warranted and clinical monitoring is recommended. |
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| methadone |
↓ R-methadone |
Concentrations of methadone were reduced when co-administered with telaprevir. No adjustment of methadone dose is required when initiating co-administration of telaprevir. However, clinical monitoring is recommended as the dose of methadone during maintenance therapy may need to be adjusted in some patients. |
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| sildenafil tadalafil vardenafil |
↑ PDE5 inhibitors | Concentrations of PDE5 inhibitors may be increased when co-administered with telaprevir. For the treatment of erectile dysfunction, sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg dose in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours can be used with increased monitoring for PDE5 inhibitor-associated adverse events. QT interval prolongation has been reported with vardenafil. Caution is warranted and clinical monitoring is recommended. Co-administration of sildenafil or tadalafil and telaprevir in the treatment of pulmonary arterial hypertension is contraindicated [ |
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| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
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| Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
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| Amiodarone Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
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| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
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| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
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| Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
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| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
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| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
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| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
|
|
|
||
|
|
|||
| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
|
|
|||
|
|
|||
| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone Iodide (including iodine- containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
|
|
|||
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
|
|
|||
|
|
|
||
|
|
|
||
| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
|
|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
|
|
|||
|
|
|||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
|
|
|||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
|
|
|||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
| |
|
| Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Amiodarone, verapamil, diltiazem | Do not exceed 10 mg simvastatin daily |
| Amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
|
|
|
|
|
|
|
Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day). |
|
|
|
|
|
|
|
Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. |
|
|
|
|
Iodide (including iodine-containing radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
|
|
|
|
- Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function. |
|
|
|
|
|
|
|
Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
|
Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4 . Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. |
|
|
|
|
|
|
|
Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. |
|
|
|
|
Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). |
|
|
|
|
- Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
|
- Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
|
- Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
|
- Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
|
- Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
|
- (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123 I, 131I, and 99mTc. |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
|
Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. |
| Interacting Drug | Interaction |
|---|---|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
|
|
||
|
|
|
|
| No fentanyl | 6.4 ± 0.0 | 6.3 ± 0.4 |
| 3 µg/kg fentanyl | 3.5 ± 1.9 (46%) | 3.1 ± 0.6 (51%) |
| 6 µg/kg fentanyl | 3.0 ± 1.2 (53%) | 2.3 ± 1.0 (64%) |
| No midazolam | 6.9 ± 0.1 | 5.9 ± 0.6 |
| 25 µg/kg midazolam | - | 4.9 ± 0.9 (16%) |
| 50 µg/kg midazolam | - | 4.9 ± 0.5 (17%) |
|
in Neuromuscular Blockade |
||||
|
|
|
|||
|
|
|
|
|
|
| 0.65 MAC 60% N2O/O2 |
26 | 123 | - | - |
| 1.25 MAC 60% N2O/O2 |
18 | 91 | - | - |
| 1.25 MAC O2 | 22 | 120 | 362 | 19 |
|
|
||
| AED Co-administered |
AED Concentration |
Topiramate Concentration |
| Phenytoin |
NC or 25% increasea
|
48% decrease |
| Carbamazepine (CBZ) |
NC |
40% decrease |
| CBZ epoxideb
|
NC |
NE |
| Valproic acid |
11% decrease |
14% decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NC at TPM doses up to 400 mg/day |
13% decrease |
|
|
|
||
|
|
|||
| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
|
|
|||
|
|
|||
| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone Iodide (including iodine- containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
|
|
|||
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
|
|
|||
|
|
|
||
|
|
|
||
| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
|
|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
|
|
|||
|
|
|||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
|
|
|||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
|
|
|||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
| Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) | VIAGRA 25 mg |
|---|---|
| Supine | 7.4 (-0.9, 15.7) |
| Standing | 6.0 (-0.8, 12.8) |
|
|
|
|
|
|
|
|
| Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) | VIAGRA 100 mg |
|---|---|
| Supine | 7.9 (4.6, 11.1) |
| Standing |
4.3 (-1.8,10.3) |
|
|
|
|
| Drug | Effect | Clinical Comment |
|---|---|---|
| ↑ Indicates increase. ↓ Indicates decrease. a The dosing recommendation for coadministration of didanosine delayed-release capsules and tenofovir disoproxil fumarate with respect to meal consumption differs from that of didanosine. See the complete prescribing information for didanosine delayed-release capsules. |
||
| ciprofloxacin |
↓ ciprofloxacin concentration |
Administer didanosine at least 2 hours after or 6 hours before ciprofloxacin. |
| delavirdine |
↓ delavirdine concentration |
Administer didanosine 1 hour after delavirdine. |
| ganciclovir |
↓ didanosine concentration |
If there is no suitable alternative to ganciclovir, then use in combination with didanosine with caution. Monitor for didanosine-associated toxicity. |
| indinavir |
↓ indinavir concentration |
Administer didanosine 1 hour after indinavir. |
| methadone |
↓ didanosine concentration |
Do not coadminister methadone with didanosine pediatric powder due to significant decreases in didanosine concentrations. If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is didanosine delayed-release capsules. Patients should be closely monitored for adequate clinical response when didanosine delayed-release capsules are coadministered with methadone, including monitoring for changes in HIV RNA viral load. |
| nelfinavir |
↓ No interacion 1 hour after didanosine |
Administer nelfinavir 1 hour after didanosine. |
| tenofovir disoproxil fumarate |
↓ didanosine concentration |
A dose reduction of didanosine to the following dosage once daily is recommended.a
|
| Drug or Drug Class | Effect | Clinical Comment |
|---|---|---|
| ↑ Indicates increase. ↓ Indicates decrease. a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of didanosine is recommended b |
||
| Drugs that may cause pancreatic toxicity |
↑ risk of pancreatitis |
Use only with extreme cautiona
|
| Neurotoxic drugs |
↑ risk of neuropathy |
Use with cautionb
|
| Antacids containing magnesium or aluminum |
↑ side effects associated with antacid components |
Use caution with didanosine tablets for oral suspension and didanosine pediatric powder for oral solution |
| Azole antifungals |
↓ ketoconazole or Itraconazole concentration |
Administer drugs such as ketoconazole or itraconazole at least 2 hours before didanosine. |
| Quinolone antibiotics (see also ciprofloxacin in Table 9) |
↓ quinolone concentration |
Consult package insert of the quinolone. |
| Tetracycline antibiotics |
↓ antibiotic concentration |
Consult package insert of the tetracycline. |
| Enzyme | Inhibitors | Inducers |
|---|---|---|
| CYP2C9 | amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast | aprepitant, bosentan, carbamazepine, phenobarbital, rifampin |
| CYP1A2 | acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton | montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking |
| CYP3A4 | alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton | armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide |
| Drug Class | Specific Drugs |
|---|---|
| Anticoagulants | argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin |
| Antiplatelet Agents | aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine |
| Nonsteroidal Anti-Inflammatory Agents | celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac |
| Serotonin Reuptake Inhibitors | citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone |
| Interacting Agents | Prescribing Recommendations |
|---|---|
| Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) | Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
| Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) | Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) |
Do not exceed 40 mg atorvastatin daily |
|
|
|
|
|
|
Significantly Reduced |
|
|
|
Significantly Reduced | When voriconazole is coadministered with efavirenz, voriconazole maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h |
|
|
|
|
|
|
Not Studied |
|
|
|
Not Studied |
|
|
|
Significantly Reduced | Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg) |
|
|
Significantly Reduced |
|
|
|
Increased | Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives |
| Fluconazole** (CYP2C9, CYP2C19 and CYP3A4 Inhibition) | Significantly Increased |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Significantly Increased |
|
|
|
Significantly Increased |
|
|
|
Significantly Increased |
|
|
|
|
|
|
|
Not Studied |
|
|
|
Not Studied |
|
|
|
AUCτ Significantly Increased; No Significant Effect on Cmax | When initiating therapy with voriconazole in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary |
| Methadone*** (CYP3A4 Inhibition) | Increased | Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed |
| Fentanyl (CYP3A4 Inhibition) | Increased | Reduction in the dose of fentanyl and other long acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate associated adverse events may be necessary [ |
| Alfentanil (CYP3A4 Inhibition) | Significantly Increased | Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole. A longer period for monitoring respiratory and other opiate associated adverse events may be necessary [ |
| Oxycodone (CYP3A4 Inhibition) | Significantly Increased | Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate associated adverse events may be necessary [ |
|
|
Increased | Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed. [ |
|
|
Significantly Increased | When initiating therapy with voriconazole in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary. |
|
|
Significantly Increased | Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin. |
| Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)** | Increased | Monitoring for adverse events related to oral contraceptives is recommended during coadministration. |
|
|
Prothrombin Time Significantly Increased | Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed. |
|
|
Significantly Increased | When initiating therapy with voriconazole in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors. |
|
|
|
|
|
|
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure) | Frequent monitoring for adverse events and toxicity related to NNRTI |
|
|
|
Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed. |
| HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition) |
|
Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed. |
|
|
|
Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed. |
| Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition) | Not Studied |
Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed. |
|
|
Not Studied |
Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed. |
| Alpha-Blocker | Simultaneous dosing of Vardenafil 5 mg and Alpha-Blocker, Placebo-Subtracted |
Dosing of Vardenafil 5 mg and Alpha-Blocker Separated by 6 Hours, Placebo-Subtracted |
|
| Terazosin 5 or 10 mg daily |
Standing SBP | -3 (-6.7, 0.1) | -4 (-7.4, -0.5) |
| Supine SBP | -4 (-6.7, -0.5) | -4 (-7.1, -0.7) | |
| Tamsulosin 0.4 mg daily |
Standing SBP Supine SBP |
-6 (-9.9, -2.1) -4 (-7.0, -0.8) |
-4 (-8.3, -0.5) -5 (-7.9, -1.7) |
| Vardenafil 10 mg Placebo-subtracted |
Vardenafil 20 mg Placebo-subtracted |
|
| Standing SBP | -4 (-6.8, -0.3) | -4 (-6.8, -1.4) |
| Supine SBP | -5 (-8.2, -0.8) | -4 (-6.3, -1.8) |
|
|
||
| albuterol, systemic and | finasteride | norfloxacin |
| inhaled | hydrocortisone | ofloxacin |
| amoxicillin | isoflurane | omeprazole |
| ampicillin, with or without | isoniazid | prednisone, prednisolone |
| sulbactam | isradipine | ranitidine |
| atenolol | influenza vaccine | rifabutin |
| azithromycin | ketoconazole | roxithromycin |
| caffeine, dietary ingestion | lomefloxacin | sorbitol |
| cefaclor | mebendazole | (purgative doses do not |
| co-trimoxazole | medroxyprogesterone | inhibit theophylline |
| (trimethoprim and | methylprednisolone | absorption) |
| sulfamethoxazole) | metronidazole | sucralfate |
| diltiazem | metoprolol | terbutaline,systemic |
| dirithromycin | nadolol | terfenadine |
| enflurane | nifedipine | tetracycline |
| famotidine | nizatidine | tocainide |
| felodipine | ||
|
|
||
| Concomitant Drug |
Effect on Concentration of Lamotrigine or Concomitant Drug |
Clinical Comment |
| Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine ↓ levonorgestrel |
Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%. |
| Carbamazepine (CBZ) and CBZ epoxide |
↓ lamotrigine ? CBZ epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase CBZ epoxide levels |
| Phenobarbital/Primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40%. |
| Valproate |
↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
| Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( |
|
| Interacting Agents | Prescribing Recommendations |
| Cyclosporine | Do not exceed 10 mg atorvastatin daily |
| Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir) | Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used. |
| % Change from Plavix (300 mg/75 mg) alone | ||||||
|---|---|---|---|---|---|---|
| Plavix plus | Cmax (ng/mL) | AUC | Platelet Inhibition |
|||
| Day 1 | Day 5 | Day 1 | Day 5 |
Day 1 | Day 5 | |
| Omeprazole |
↓46% | ↓42% | ↓45% | ↓40% | ↓39% | ↓21% |
| Pantoprazole 80 mg | ↓24% | ↓28% | ↓20% | ↓14% | ↓15% | ↓11% |
|
|
|
|
|
|
+82% |
|
|
|
+135% |
|
| Drug or Drug Class | Effect |
|---|---|
| Potential impact: Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. | |
| Calcium Carbonate Ferrous Sulfate |
Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. |
| Orlistat | Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
| Bile Acid Sequestrants -Colesevelam -Cholestyramine -Colestipol Ion Exchange Resins -Kayexalate -Sevelamer |
Bile acid sequestrants and ion exchange resins are known to decrease levothyroxine absorption. Administer levothyroxine at least 4 hours prior to these drugs or monitor thyrotropin-stimulating hormone (TSH) levels. |
| Other drugs: Sucralfate Antacids - Aluminum & Magnesium Hydroxides - Simethicone |
|
| Drugs That May Increase Serum Thyroxine-Binding Globulin (TBG) Concentration | Drugs That May Decrease Serum TBG Concentration |
|---|---|
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
| Potential impact |
|
| Salicylates (> 2 g/day) | Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total T4 levels may decrease by as much as 30%. |
| Other drugs: Furosemide (> 80 mg IV) Heparin Hydantoins Non-Steroidal Anti-inflammatory Drugs - Fenamates - Phenylbutazone |
|
| Drug or Drug Class | Effect |
|---|---|
| Potential impact: Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. | |
| Carbamazepine Hydantoins |
Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total and FT4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. Close monitoring of thyroid hormone parameters is recommended. |
| Other drugs: Phenobarbital Rifampin |
|
| Drug or Drug Class | Effect |
|---|---|
| Potential impact: Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. | |
| Beta-adrenergic antagonists (e.g., Propranolol > 160 mg/day) |
In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. |
| Glucocorticoids (e.g., Dexamethasone ≥ 4 mg/day) |
Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (See above). |
| Other: Amiodarone |
|
|
|
|
| Cyclosporine | Do not exceed 10 mg atorvastatin daily |
| Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir) | Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used. |
| Table 5 Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours in healthy adult subjects (n=24) | ||
|
|
(Peak plasma concentration) |
(Extent of systemic exposure) |
| Erythromycin (500 mg every 8 hrs) |
+82% | +109% |
| Ketoconazole (400 mg once daily) |
+135% | +164% |
| Drug | Effect | |
|---|---|---|
| Phenylephrine with prior administration of monoamine oxidase inhibitors (MAOI). |
Cardiac pressor response potentiated. May cause acute hypertensive crisis. |
|
| Phenylephrine with tricyclic anti-depressants. |
Pressor response increased. |
|
| Phenylephrine with ergot alkaloids. |
Excessive rise in blood pressure. |
|
| Phenylephrine with bronchodilator sympathomimetic agents and with epinephrine or other sympathomimetics. |
Tachycardia or other arrhythmias may occur. | |
| Phenylephrine with prior administration of propranolol or other β-adrenergic blockers. |
Cardiostimulating effects blocked. | |
| Phenylephrine with atropine sulfate. |
Reflex bradycardia blocked; pressor response enhanced. |
|
| Phenylephrine with prior administration of phentolamine or other α-adrenergic blockers. |
Pressor response decreased. | |
| Phenylephrine with diet preparations, such as amphetamines or phenylpropanolamine. |
Synergistic adrenergic response. |
|
|
(Peak plasma concentration) |
(Extent of systemic exposure) |
|---|---|---|
| Erythromycin (500 mg every 8 hrs) |
+82% | +109% |
| Ketoconazole (400 mg once daily) |
+135% | +164% |
|
|
|
| Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol |
Contraindicated with VYTORIN |
| Verapamil, diltiazem | Do not exceed 10/10 mg VYTORIN daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 10/20 mg VYTORIN daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
| Drug Class | Examples of Drugs Within Class |
|---|---|
| Antiarrhythmics | Disopyramide, mexiletine, quinidine, tocainide |
| Antibiotics | Chloramphenicol, clarithromycin, dapsone, doxycycline; Fluoroquinolones (such as ciprofloxacin) |
| Oral Anticoagulants | Warfarin |
| Anticonvulsants | Phenytoin |
| Antimalarials | Quinine |
| Azole Antifungals | Fluconazole, itraconazole, ketoconazole |
| Antipsychotics | Haloperidol |
| Barbiturates | Phenobarbital |
| Benzodiazepines | Diazepam |
| Beta-Blockers | Propanolol |
| Calcium Channel Blockers | Diltiazem, nifedipine, verapamil |
| Cardiac Glycoside Preparations | Digoxin |
| Corticosteroids | Prednisone |
| Fibrates | Clofibrate |
| Oral Hypoglycemics | Sulfonylureas (e.g., glyburide, glipizide) |
| Hormonal Contraceptives/ Progestins | Ethinyl estradiol, levonorgestrel |
| Immunosuppressants | Cyclosporine, tacrolimus |
| Methylxanthines | Theophylline |
| Narcotic analgesics | Methadone |
| Phophodiesterase-5 (PDE-5) Inhibitors | Sildenafil |
| Thyroid preparations | Levothyroxine |
| Tricyclic antidepressants | Amitriptyline, nortriptyline |
|
|
|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
|
|
|
||
|
|
|||
| Dopamine/Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day). | ||
|
|
|||
|
|
|||
| Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | ||
|
|
|||
| Amiodarone Iodide (including iodine- containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | ||
|
|
|||
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | ||
|
|
|||
|
|
|
||
|
|
|
||
| Clofibrate | Androgens / Anabolic Steroids | ||
| Estrogen-containing oral | Asparaginase | ||
| contraceptives | Glucocorticoids | ||
| Estrogens (oral) | Slow-Release Nicotinic Acid | ||
| Heroin / Methadone | |||
| 5-Fluorouracil | |||
| Mitotane | |||
| Tamoxifen | |||
|
|
|||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4, is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | ||
|
|
|||
|
|
|||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | ||
|
|
|||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decrease the peripheral conversion of T4 to T3, Ieading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | ||
|
|
|||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | ||
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | ||
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | ||
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | ||
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | ||
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | ||
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | ||
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | ||
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | ||
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | ||
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms. | ||
|
|
|
|
|
|
||
| Dopamine / Dopamine Agonists Glucocorticoids Octreotide |
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day). | |
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|
||
|
|
||
| Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide |
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T4 and T3 levels and increase TSH, although all values remain within normal limits in most patients. | |
|
|
||
| Amiodarone Iodide (including iodine-containing Radiographic contrast agents) |
Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. | |
|
|
||
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate |
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. | |
|
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||
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|
|
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen |
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid |
|
|
|
||
| Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day) |
Administration of these agents with levothyroxine results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total-T4 levels may decrease by as much as 30%. | |
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||
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|
||
| Carbamazepine Hydantoins Phenobarbital Rifampin |
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. | |
|
|
||
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU) |
Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (see above). | |
|
|
||
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives |
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. | |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline) |
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. | |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin |
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. | |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. | |
| Cytokines - Interferon-α - Interleukin-2 |
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. | |
| Growth Hormones - Somatrem - Somatropin |
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. | |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. | |
| Methylxanthine Bronchodilators - (e.g., Theophylline) |
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. | |
| Radiographic Agents | Thyroid hormones may reduce the uptake of 123I, 131I, and 99mTc. | |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. | |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics |
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms. | |
|
|
(Peak plasma concentration) |
(Extent of systemic exposure) |
|---|---|---|
| Erythromycin (500 mg every 8 hrs) |
+82% | +109% |
| Ketoconazole (400 mg once daily) |
+135% | +164% |
|
|
|
|
|
Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
|
|
Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) | Do not exceed 40 mg atorvastatin daily |
|
|
|
| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine, danazol | Do not exceed 10 mg simvastatin daily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Diltiazem | Do not exceed 40 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (> 1 quart daily) |
|
|
|
| Multivalent cation-containing products including antacids, metal cations or didanosine | Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products ( |
| Warfarin | Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents | Carefully monitor blood glucose ( |
| ↓= Decreased (induces lamotrigine glucuronidation). | ||
| ↑= Increased (inhibits lamotrigine glucuronidation). | ||
| ? = Conflicting data. | ||
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|
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|
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|
|
|
|
|
|
|
|
|
|
|
|
|
| Antiarrhythmics | digoxin, dofetilide, quinidine, disopyramide |
| Anticonvulsants | carbamazepine |
| Anti-HIV Agents | indinavir, ritonavir, saquinavir, maraviroc |
| Antineoplastics | busulfan, docetaxel, vinca alkaloids |
| Antipsychotics | pimozide |
| Benzodiazepines | alprazolam, diazepam, midazolam, |
| Calcium Channel Blockers | dihydropyridines (including nisoldipine and felodipine), verapamil |
| Gastrointestinal Motility Agents | cisapride |
| HMG CoA-Reductase Inhibitors | atorvastatin, cerivastatin, lovastatin, simvastatin |
| Immunosuppressants | Cyclosporine, tacrolimus, sirolimus |
| Oral Hypoglycemics | oral hypoglycemics (repaglinide) |
| Opiate Analgesics | fentanyl, levacetylmethadol (levomethadyl), methadone |
| Polyene Antifungals | amphotericin B |
| Other | ergot alkaloids, halofantrine, alfentanil, buspirone, methylprednisolone, budesonide, dexamethasone, fluticasone, warfarin, cilostazol, eletriptan, fexofenadine, loperamide |
|
|
|
| Anticonvulsants | carbamazepine, phenobarbital, phenytoin |
| Anti-HIV Agents | nevirapine, efavirenz |
| Antimycobacterials | isoniazid, rifabutin, rifampin |
| Gastric Acid Suppressors/Neutralizers | antacids, H2-receptor antagonists, proton pump inhibitors |
|
|
|
| Macrolide Antibiotics | clarithromycin, erythromycin |
| Anti-HIV Agents | indinavir, ritonavir |
| Antipsychotics | pimozide |
| Antiarrhythmics | dofetilide, quinidine |
| Benzodiazepines | oral midazolam |
| Calcium Channel Blockers | Nisoldipine, felodipine |
| Ergot Alkaloids | dihydroergotamine, ergotamine, ergometrine (ergonovine), methylergometrine (methylergonovine) |
| Gastrointestinal Motility Agents | cisapride |
| HMG CoA-Reductase Inhibitors | lovastatin, simvastatin |
| Opiate Analgesics | levacetylmethadol (levomethadyl), methadone |
|
|
|
|
|
Avoid atorvastatin |
| HIV protease inhibitor (lopinavir plus ritonavir) | Use with caution and lowest dose necessary |
|
|
Do not exceed 20 mg atorvastatin daily |
| HIV protease inhibitor (nelfinavir) | Do not exceed 40 mg atorvastatin daily |
| Concomitant Drug |
Effect on Concentration of Lamotrigine or Concomitant Drug |
Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
↓ lamotrigine ↓ levonorgestrel |
Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%. |
| Carbamazepine (CBZ) and CBZ epoxide |
↓ lamotrigine ? CBZ epoxide |
Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase CBZ epoxide levels |
| Phenobarbital/Primidone |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) |
↓ lamotrigine |
Decreased lamotrigine concentration approximately 40%. |
| Rifampin |
↓ lamotrigine |
Decreased lamotrigine AUC approximately 40%. |
| Valproate |
↑ lamotrigine ? valproate |
Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
|
|
|
|
|
| a Should be administered at least 4 hours prior to WELCHOL | |
|
b No significant alteration of warfarin drug levels with warfarin and WELCHOL coadministration in an |
|
| c Cyclosporine levels should be monitored and, based on theoretical grounds, cyclosporine should be administered at least 4 hours prior to WELCHOL. | |
| Drugs with a known interaction with colesevelam | Cyclosporinec, glyburidea, levothyroxinea, and oral contraceptives containing ethinyl estradiol and norethindronea |
| Drugs with postmarketing reports consistent with potential drug-drug interactions when coadministered with WELCHOL | phenytoina, warfarinb |
| Drugs that do not interact with colesevelam based on |
cephalexin, ciprofloxacin, digoxin, warfarinb fenofibrate, lovastatin, metformin, metoprolol, pioglitazone, quinidine, repaglinide, valproic acid, verapamil |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
|
Decreased Lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide |
|
Addition of carbamazepine decreases Lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels. | |
| Phenobarbital/Primidone | ↓ Lamotrigine | Decreased Lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ Lamotrigine | Decreased Lamotrigine concentration approximately 40%. |
| Rifampin | ↓ Lamotrigine | Decreased Lamotrigine AUC approximately 40%. |
| Valproate |
|
Increased Lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
|
|
||
| AED Co-administered |
AED Concentration |
Topiramate Concentration |
| Phenytoin |
NC or 25% increasea
|
48% decrease |
| Carbamazepine (CBZ) |
NC |
40% decrease |
| CBZ epoxideb
|
NC |
NE |
| Valproic acid |
11% decrease |
14% decrease |
| Phenobarbital |
NC |
NE |
| Primidone |
NC |
NE |
| Lamotrigine |
NC at TPM doses up to 400 mg/day |
13% decrease |
| Concomitant Drug | Effect on Concentration of Lamotrigine or Concomitant Drug | Clinical Comment |
| Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel |
|
Decreased Lamotrigine levels approximately 50%. |
| ↓ levonorgestrel | Decrease in levonorgestrel component by 19%. | |
| Carbamazepine (CBZ) and CBZ epoxide |
|
Addition of carbamazepine decreases Lamotrigine concentration approximately 40%. |
| ? CBZ epoxide | May increase CBZ epoxide levels. | |
| Phenobarbital/Primidone | ↓ Lamotrigine | Decreased Lamotrigine concentration approximately 40%. |
| Phenytoin (PHT) | ↓ Lamotrigine | Decreased Lamotrigine concentration approximately 40%. |
| Rifampin | ↓ Lamotrigine | Decreased Lamotrigine AUC approximately 40%. |
| Valproate |
|
Increased Lamotrigine concentrations slightly more than 2-fold. |
| ? valproate | Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients. |
|
|
|
|
|
|
| Dopamine / Dopamine Agonists Glucocorticoids Octreotide
|
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day). |
|
|
|
|
|
|
| Aminoglutethimide Amiodarone Iodide(including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide
|
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. 4 3 |
|
|
|
| Amiodarone Iodide(including iodine-containing Radiographic contrast agents)
|
Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis. |
|
|
|
| Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate
|
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function. |
|
|
|
|
|
|
| Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen
|
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
|
|
|
|
| Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)
|
Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T , and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. 4 4 4 4 3 4 4 4 |
|
|
|
|
|
|
| Carbamazepine Hydantoins Phenobarbital Rifampin
|
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. 4 |
|
|
|
| Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)
|
Administration of these enzyme inhibitors decreases the peripheral conversion of T to T , leading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T and T levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). 4 3 3 4 3 4 3 4 3 4 |
|
|
|
| Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives
|
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly. |
| Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)
|
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements. |
| Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin
|
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued. |
| Cardiac Glycosides | Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced. |
| Cytokines - Interferon-α - Interleukin-2
|
Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction. |
| Growth Hormones - Somatrem - Somatropin
|
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone. |
| Ketamine | Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended. |
| Methylxanthine Bronchodilators - (e.g., Theophylline)
|
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved. |
| Radiographic Agents | Thyroid hormones may reduce the uptake of I, I, and Tc. 123 131 99m |
| Sympathomimetics | Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease. |
| Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics
|
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms. |
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3 mg twice daily |
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| albuterol, | famotidine | nizatidine |
| systemic and inhaled | felodipine | norfloxacin |
| amoxicillin | finasteride | ofloxacin |
| ampicillin, | hydrocortisone | omeprazole |
| with or without | isoflurane | prednisone, prednisolone |
| sulbactam | isoniazid | ranitidine |
| atenolol | isradipine | rifabutin |
| azithromycin | influenza vaccine | roxithromycin |
| caffeine, | ketoconazole | sorbitol |
| dietary ingestion | lomefloxacin | (purgative doses do not |
| cefaclor | mebendazole | inhibit theophylline |
| co-trimoxazole | medroxyprogesterone | absorption) |
| (trimethoprim and | methylprednisolone | sucralfate |
| sulfamethoxazole) | metronidazole | terbutaline, systemic |
| diltiazem | metoprolol | terfenadine |
| dirithromycin | nadolol | tetracycline |
| enflurane | nifedipine | tocainide |
|
|
|
| Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol | Contraindicated with simvastatin |
| Verapamil, diltiazem, dronedarone | Do not exceed 10 mg simvastatin daily |
| Amiodarone, amlodipine, ranolazine | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid grapefruit juice |
| albuterol, systemic and | finasteride | norfloxacin |
| inhaled | hydrocortisone | ofloxacin |
| amoxicillin | isoflurane | omeprazole |
| ampicillin, with or without | isoniazid | prednisone, prednisolone |
| sulbactam | isradipine | ranitidine |
| atenolol | influenza vaccine | rifabutin |
| azithromycin | ketoconazole | roxithromycin |
| caffeine, dietary ingestion | lomefloxacin | sorbitol |
| cefaclor | mebendazole | (purgative doses do not |
| co-trimoxazole | medroxyprogesterone | inhibit theophylline |
| (trimethoprim and | methylprednisolone | absorption) |
| sulfamethoxazole) | metronidazole | sucralfate |
| diltiazem | metoprolol | terbutaline,systemic |
| dirithromycin | nadolol | terfenadine |
| enflurane | nifedipine | tetracycline |
| famotidine | nizatidine | tocainide |
| felodipine |
| Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) | VIAGRA 25 mg |
| Supine | 7.4 (-0.9, 15.7) |
| Standing | 6.0 (-0.8, 12.8) |
| Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg) | VIAGRA 100 mg |
| Supine | 7.9 (4.6, 11.1) |
| Standing |
4.3 (-1.8,10.3) |
|
|
|
| Antacids, sucralfate, multivitamins, and other products containing multivalent cations | Moxifloxacin absorption is decreased. Administer AVELOX Tablet at least 4 hours before or 8 hours after these products. ( |
| Warfarin | Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. ( |
| Class IA and Class III antiarrhythmics: | Proarrhythmic effect may be enhanced. Avoid concomitant use. ( |
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| Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone | Avoid simvastatin |
| Gemfibrozil, cyclosporine, danazol | Do not exceed 10 mg simvastatin daily |
| Amiodarone, verapamil | Do not exceed 20 mg simvastatin daily |
| Grapefruit juice | Avoid large quantities of grapefruit juice (>1 quart daily) |
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| Multivalent cation-containing products including antacids, metal cations or didanosine |
Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. Do not coadminister the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( |
| Warfarin |
Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( |
| Antidiabetic agents |
Carefully monitor blood glucose ( |